CN101730526A - Nanoparticle comprising rapamycin and albumin as anticancer agent - Google Patents

Abstract

The present invention features methods for treating, stabilizing, preventing, and/or delaying cancer by administering nanoparticles that comprise rapamycin or a derivative thereof. The invention also provides compositions (e.g., unit dosage forms) comprising nanoparticles that comprise a carrier protein and rapamycin or a derivative thereof. The invention further provides combination therapy methods of treating cancer comprising administering to an individual an effective amount of nanoparticles that comprise rapamycin or a derivative thereof and a second therapy.

Description

Comprise rapamycin and albuminous nano-particle as anticarcinogen

The cross reference of related application

The application requires following U.S. Provisional Application No. benefit: the 60/905th of proposition on March 7th, 2007, No. 669, the 60/905th of submission on March 7th, 2007, No. 734, the 60/905th of submission on March 7th, 2007, No. 662, the 60/905th of submission on March 7th, 2007, No. 735, the 60/905th of submission on March 7th, 2007, No. 672, the 60/905th of submission on March 7th, 2007, No. 787, the 60/905th of submission on March 7th, 2007, No. 663, the 60/905th of submission on March 7th, 2007, No. 767, the 60/905th of submission on March 7th, 2007, No. 750, the 60/923rd of submission on April 13rd, 2007, submit in No. 248 and on April 13rd, 2007 the 60/923rd, No. 456, and wherein the whole of each openly are hereby incorporated by.

Technical field

The application relates to and uses the nano-particle treatment comprise rapamycin or its derivant, stable, prevention and/or postpone method for cancer and compositions.The application also provides the combinational therapeutic methods of treatment cancer, and it comprises the nano-particle that contains rapamycin or its derivant and second therapy that gives individual effective dose.

Background

It is serious problems in the treatment of cancer that a large amount of tumors is not replied medicine and/or radiotherapy.In fact, although obtained some progress in the chemotherapy field, the problems referred to above are that the human cancer of many common form is still resisted the one of the main reasons that effective chemotherapy is intervened.

Now, mainly use a kind of in three kinds of therapies or unite and treat cancer: operation, radiation and chemotherapy.Operation is a traditional method, and wherein all or part of tumor is removed from body.Usually, operation is only effective than early-stage cancer to treatment.For example the tumor at breast, colon and skin place is effective sometimes though operation is positioned at some positions in removal, and it can not be used for the treatment of and is positioned at untouchable other the regional tumor of operator, can not be used for the treatment of dissemination tumor situation such as leukemia.For the cancer individuality more than 50%, they no longer are the candidates of effective operative treatment by diagnosis the time.Operation method can increase the intra-operative tumor by sanguimotor transfer.Most of cancer individualities are not to die from cancer when diagnosis or operation, but die from cancer metastasis and recurrence.

Other treatment also usually is invalid.Radiotherapy only shows as the effectively individual of clinical localization disease to the cancer early and middle portion, and for invalid with the terminal cancer that shifts.Radiotherapy generally is used to contain the localized area of the object body of abnormality proliferation sex organization, purpose be make the dosage maximization that abnormal structure absorbs and make near the dosage that absorbs of normal structure minimize.Yet giving abnormal structure with the therapeutic radiation selectivity is difficult (if not cannot).Therefore, in whole therapeutic process, also be exposed to the potential damage dosage of radiation with abnormal structure approaching normal structure.Therefore, radiotherapy technology destroys the effect of abnormality proliferation cell by near Normocellular relevant cell toxic action is cancelled.Therefore, radiotherapy technology has inherent narrow therapeutic index, and this makes most of tumors by insufficient treatment.Even best radiotherapy technology can cause also that incomplete tumor is dwindled, tumor recurrence, increase tumor load and induce the tumor that radiation is had resistance.

Chemotherapy comprises the destruction of cellular replication or cellular metabolism.Chemotherapy can be effectively, but has serious adverse, for example, feels sick, leukopenia, alopecia, loses weight and other toxic action.Because the side effect of extreme toxicity, many cancer individualities can not successfully be finished whole chemotherapy regimen.The quality of life of the inductive side effect appreciable impact of chemotherapy individuality, and can obviously influence individual compliance to treatment.In addition, relevant with chemotherapeutics adverse side effect generally is to give the main dose-limiting toxicity in these medicines (dose-limitingtoxicity).For example, mucositis is one of main dose-limiting toxicity of several anticarcinogens, and described anticarcinogen comprises 5-FU, methotrexate and antitumor antibiotics such as doxorubicin.If many in the inductive side effect of these chemotherapy seriously can cause hospitalization, perhaps need with the analgesic treatment with treatment pain.Certain cancers is individual owing to the Intolerance to chemotherapy is died from chemotherapy.The extreme side effect of anticarcinogen causes by the targeting specific of these medicines is bad.Medicine cycles through individual most of normal organs and target tumor.Cause the bad effect that also reduces chemotherapy of target-specific of side effect, because only some medicine is by correct targeting.The effect of chemotherapy is owing to the retentivity difference of anticarcinogen in the target tumor is further reduced.

Another problem relevant with chemotherapy is drug-fast development.Drug resistance is to give the title that disease does not respond to the situation of one or more medicines.Drug resistance can be inherent, this means that disease never produces a kind of medicine or multiple medicine to reply, and perhaps can be acquired, this means that disease stops this disease before produced its a kind of medicine of replying or multiple medicine to reply.The therapeutic alliance that has comprised combined chemotherapy has two kinds of possible benefits avoiding the resisting cell appearance and kill the cell that drug resistance is arranged of preexist.

Because the limitation of treatment of cancer at present, the order of severity of vegetation, tumor and cancer and range still exist significant interest and demand to treatment, stable, prevention and/or other or the optional therapy that postpone cancer.Preferably, this treatment overcomes the shortcoming of present operation, chemotherapy and radiation treatment.

The invention summary

The invention provides and use the nano-particle treatment method for cancer that comprises the rapamycin or derivatives thereof.Therefore, in some embodiments, the invention provides method for cancer in the treatment individuality, it is implemented by the compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein that gives individuality (for example people) effective dose.In some embodiments, cancer is early cancer, non-metastatic carcinoma, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists situation cancer (cancer in anadjuvant setting), newly assists situation cancer (cancer in a neoadjuant setting) or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is solid tumor (solid tumor).In some embodiments, cancer is not solid tumor (just except a solid tumor).In some embodiments, cancer is plasmocytoma (plasmacytoma).In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (carcinoma) (that is, except a carcinoma).In some embodiments, cancer is not colon cancer (that is, except a colon cancer).In some embodiments, cancer is not breast carcinoma (that is, except a breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or is prevented.

In some embodiments, the amount of rapamycin or derivatives thereof is to arrive within the scope of about 540mg at about 54mg in the effective dose compositions, and for example approximately 180mg arrives in about 270mg scope, or about 216mg.In some embodiments, the rapamycin or derivatives thereof is that parenteral gives (for example intravenous gives).In some embodiments, do not give taxane (that is, except taxane) to individuality.In some embodiments, the taxane that gives is not a nano-particle taxane compositions.In some embodiments, the rapamycin or derivatives thereof is to be given only forms of pharmacologically active agents that individuality is used for the treatment of cancer.In some embodiments, give rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is albumin such as human serum albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

The present invention also provides the pharmaceutical composition that is used for the treatment of cancer unit dosage forms for example.Therefore, in some embodiments, the invention provides the pharmaceutical composition (for example pharmaceutical composition of unit dosage forms) that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein.In some embodiments, compositions also comprises pharmaceutically acceptable carrier.In various embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say, except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say, except carcinoma).In some embodiments, cancer is not colon cancer (that is to say, except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say, except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or is prevented.

In some embodiments, the amount of rapamycin or derivatives thereof in compositions (for example dosage or unit dosage forms) be at about 54mg in about 540mg scope, for example approximately 180mg in about 270mg scope, or about 216mg.In some embodiments, carrier is to be suitable for parenteral to give (for example intravenous gives).In some embodiments, taxane is not included in the compositions.In some embodiments, the rapamycin or derivatives thereof is included in the only forms of pharmacologically active agents that is used for the treatment of cancer in the compositions.In some embodiments, compositions comprises rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is an albumin, for example the human serum albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

Also in addition on the one hand, the present invention includes and have following test kit: (i) compositions, it comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein, (ii) the description of using in the treatment cancer.In various embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not a colon cancer.In some embodiments, cancer is not a breast carcinoma.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or is prevented.

In some embodiments, in the scope of about 540mg, for example approximately 180mg arrives in the scope of about 270mg the amount of rapamycin or derivatives thereof at about 54mg in test kit, or about 216mg.In some embodiments, the rapamycin or derivatives thereof is given (for example intravenous) by parenteral.In some embodiments, test kit does not contain taxane.In some embodiments, the rapamycin or derivatives thereof is included in the only forms of pharmacologically active agents that is used for the treatment of cancer in the test kit.In some embodiments, test kit comprises another forms of pharmacologically active agents for the treatment of cancer.In some embodiments, other forms of pharmacologically active agents is a chemotherapeutics.In some embodiments, test kit comprises rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is an albumin, for example the human serum albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in the compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

The present invention also provides and uses conjoint therapy treatment method for cancer.The invention provides the treatment method for cancer, it comprises: first therapy of the compositions of the nano-particle that a) gives to contain rapamycin or derivatives thereof and carrier protein comprising of individual effective dose, and b) second therapy, for example perform the operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy and/or chemotherapy (for example, to useful one or more chemical compounds or its pharmaceutically acceptable salt of treatment cancer).

In some embodiments, the invention provides and in individuality, treat method for cancer, it comprises and gives individuality: a) compositions of effective dose, it comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein, b) at least a other chemotherapeutics of effective dose.In some embodiments, chemotherapeutics is any (with being selected from following substances in some embodiments) in the following substances: the regulator of taxane, antimetabolite (comprising nucleoside analog), the medicament based on platinum, alkylating agent, tyrosine kinase inhibitor, anthracycline antibiotics, vinca alkaloids, proteasome inhibitor, HER2/neu regulator, EGFR, regulator and the topology isomerase inhibitors of VEGFR.In some embodiments, chemotherapeutics is based on the medicament such as the carboplatin of platinum.In some embodiments, chemotherapeutics is that the HER2/neu regulator is (as the inhibitor of HER2/neu, for example

).In some embodiments, chemotherapeutics is that the regulator of EGFR is (as the inhibitor of EGFR, for example

(

)).In some embodiments, chemotherapeutics be anti-VEGF antibodies (as bevacizumab, for example, ).In some embodiments, the Nanoparticulate compositions of effective dose and anti-VEGF antibodies suppress cell propagation synergistically or shift.In some embodiments, the chemotherapeutics influence relates to the signal transduction path of rapamycin target.In some embodiments, chemotherapeutics has influenced the signal transduction path (as the PI3K/Akt signal transduction path) that relates to mTOR.In some embodiments, do not give individual taxane.In some embodiments, the taxane that is given is not in Nanoparticulate compositions.

In some embodiments, the compositions and the chemotherapeutics that comprise the nano-particle that contains rapamycin or derivatives thereof and carrier protein give simultaneously, perhaps give in same compositions or give with the compositions of separating.In some embodiments, the Nanoparticulate compositions and the chemotherapeutics that comprise rapamycin or derivatives thereof and carrier protein give in succession, for example, and Nanoparticulate compositions or before the chemotherapeutics administration, give or after it, give.In some embodiments, what comprise the Nanoparticulate compositions of rapamycin or derivatives thereof and carrier protein and chemotherapeutics is simultaneous, for example, overlaps each other during the administration of Nanoparticulate compositions and during the administration of chemotherapeutics.In some embodiments, comprise the Nanoparticulate compositions of rapamycin or derivatives thereof and carrier protein and chemotherapeutics give be not simultaneous.For example, in some embodiments, comprise rapamycin or derivatives thereof and carrier protein Nanoparticulate compositions give before giving chemotherapeutics, stop.In some embodiments, chemotherapeutics gave before the Nanoparticulate compositions that comprises rapamycin or derivatives thereof and carrier protein is given stop.

In some embodiments, provide and in individuality, treated method for cancer, it comprises: a) first therapy, it comprises and gives the compositions that individuality comprises nano-particle, described nano-particle contains rapamycin or derivatives thereof and carrier protein, and b) second therapy, it comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy or its combination.In some embodiments, second therapy is a hormonotherapy.In some embodiments, second therapy is a radiotherapy.In some embodiments, second therapy is operation.In some embodiments, first therapy was carried out before second therapy.In some embodiments, first therapy is carried out after second therapy.

In some embodiments, the cancer by the conjoint therapy treatment is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say, except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say, except carcinoma).In some embodiments, cancer is not colon cancer (that is to say, except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say, except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or is prevented.

In some embodiments, in the scope of about 540mg, for example approximately 180mg arrives in the scope of about 270mg the rapamycin or derivatives thereof amount in the effective dose compositions of using in conjoint therapy at about 54mg, or about 216mg.In some embodiments, the rapamycin or derivatives thereof is given (for example intravenous) by parenteral.In some embodiments, do not give individual taxane (that is to say) except taxane.In some embodiments, the taxane that gives is not a nano-particle taxane compositions.In some embodiments, give rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is albumin such as human serum albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in the compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

The present invention also provides in the therapeutic alliance of treatment cancer for example unit dosage forms of useful pharmaceutical composition.Therefore, in some embodiments, the invention provides the pharmaceutical composition (for example pharmaceutical composition of unit dosage forms) that uses in conjoint therapy, it comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein.In some embodiments, pharmaceutical composition comprises: a) nano-particle, it comprises the nano-particle of rapamycin or derivatives thereof and carrier protein, and b) at least a other therapeutic agent.In some embodiments, other therapeutic agent comprises chemotherapeutics.In some embodiments, other therapeutic agent comprises the hormone therapy agent.In some embodiments, compositions also comprises pharmaceutically acceptable carrier.In some embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say, except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say, except carcinoma).In some embodiments, cancer is not colon cancer (that is to say, except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say, except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or prevents.

In some embodiments, in about 540mg scope, for example approximately 180mg arrives in about 270mg scope the rapamycin or derivatives thereof amount in the compositions of using in conjoint therapy at about 54mg, or about 216mg.In some embodiments, carrier is suitable for parenteral and gives (for example intravenous gives).In some embodiments, in compositions, do not comprise taxane.In some embodiments, the rapamycin or derivatives thereof is the only forms of pharmacologically active agents that is used for the treatment of cancer that comprises in the compositions part of the test kit that contains the description of using compositions and another kind of therapy (for example, as).

In some embodiments, compositions comprises rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is for example human serum albumin of albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in the compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

Aspect another, the present invention includes test kit, it contains: (i) compositions, it comprises the operation instructions in nano-particle that contains rapamycin or derivatives thereof and carrier protein and the conjoint therapy of (ii) the treating cancer.The present invention also provides the test kit that uses rapamycin described herein (or its derivant) compositions in the environment of therapeutic alliance.For example, remove another therapeutic combination beyond the region of objective existence, test kit can also provide such compositions.In some embodiments, description provides the description of first and second therapies, and wherein first therapy or second therapy comprise the compositions of the nano-particle that comprises rapamycin or derivatives thereof and carrier protein.In some embodiments, test kit also comprises at least a other therapeutic agent.In some embodiments, other therapeutic agent comprises chemotherapeutics.In some embodiments, other therapeutic agent comprises the hormone therapy agent.In some embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say, except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say, except carcinoma).In some embodiments, cancer is not colon cancer (that is to say, except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say, except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or prevents.

In some embodiments, in about 540mg scope, for example approximately 180mg arrives in about 270mg scope the amount of the rapamycin or derivatives thereof that uses in the conjoint therapy at about 54mg, or about 216mg.In some embodiments, rapamycin or derivatives thereof parenteral gives (for example, intravenous).In some embodiments, test kit does not contain taxane.In some embodiments, the rapamycin or derivatives thereof is the only forms of pharmacologically active agents that is used for the treatment of cancer that comprises in test kit.In some embodiments, test kit comprises the forms of pharmacologically active agents of another treatment cancer.In some embodiments, other forms of pharmacologically active agents is a chemotherapeutics.In some embodiments, test kit comprises rapamycin.In some embodiments, compositions comprises the rapamycin or derivatives thereof of about form of nanoparticles more than 50%.In some embodiments, carrier protein is albumin such as human serum albumin.In some embodiments, the average diameter of nano-particle is not more than about 200nm (for example being not more than about 100nm) in the compositions.In some embodiments, Nanoparticulate compositions is aseptic filtrable.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in nano-particle.In some embodiments, the weight ratio of carrier protein and rapamycin or derivatives thereof is about below 18: 1 in Nanoparticulate compositions.

The present invention also provides any described compositions (compositions that for example comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein) to be used for any application described herein, is being used as under the situation of medicine and/or is being used under the situation of medicine manufacturing no matter be.The goods that the unit dosage forms of compositions described herein also are provided, comprised the present composition or unit dosage forms with suitable packing (for example, bottle or container comprise the bottle of sealing or the bottle or the container of container and sterile sealing) and comprise the test kit of described unit dosage forms.The present invention also provides and has made and use as in these method for compositions described herein.

Should be understood that a kind of, some or all of character at various embodiments described herein can merge and forms other embodiment of the present invention.

The accompanying drawing summary

Fig. 1 is a table of listing the intravenous drug kinetic parameter of containing of rapamycin of albuminous nanoparticle formulations (being called the Nab-rapamycin hereinafter).

Fig. 2 A is the figure of Cmax (Cmax) and dosage, and it shows for the Nab--rapamycin is linear.

Fig. 2 B is the figure of area under curve (AUC) and dosage, and it shows for the Nab-rapamycin is linear.

Fig. 2 C is the figure of Vss and dosage, and it shows the possible saturable volume (possible saturable volume) that distributes for the Nab-rapamycin.

Fig. 2 D is presented at intravenous under the dosage level of 15mg/kg, 30mg/kg and 45mg/kg to give the figure that Nab-rapamycin haemoconcentration and the logarithm of time-linearity are drawn behind the rat.

Fig. 3 A is the figure of the anti-tumor activity of Nab-rapamycin in the mice with MX-I breast tumor xenograft.

Fig. 3 B is after giving Nab-rapamycin or saline, the figure that loses weight in the mice with MX-I breast tumor xenograft.

Fig. 4 is presented at Abraxane in the mice with HT29 colon tumor xenograft ^TM, Nab-rapamycin and Nab-rapamycin associating Abraxane ^TMThe figure of anti-tumor activity.

Fig. 5 A is the figure that is presented at the anti-tumor activity of Nab-rapamycin in the mice with HT29 colon tumor xenograft.

Fig. 5 B be presented at give Nab-rapamycin or DMSO after, the figure that in mice, loses weight with HT29 colon tumor xenograft.

Fig. 6 A is the figure that shows the anti-tumor activity of Nab-rapamycin in the mice with HCT-116 colon tumor xenograft.

Fig. 6 B be presented at give Nab-rapamycin or saline after, the figure that in mice, loses weight with HCT-116 colon tumor xenograft.

Fig. 7 is the figure that shows the anti-tumor activity of Nab-rapamycin in the mice with MM1S multiple myeloma tumor xenogeneic graft.

Detailed Description Of The Invention

The invention provides use and comprise the nano particle treatment of rapamycin or derivatives thereof and carrier protein (for example albumin) or method, composition and the kit of pre-anti-cancer. The present invention also is provided at method, composition and the kit of using in the conjoint therapy, and its use comprises nano particle treatment or the pre-anti-cancer of rapamycin or derivatives thereof and carrier protein (for example albumin). In these compositions any can be used for the treatment of, stablizes, prevents and/or postpone cancer.

Particularly, comprising the albuminous nano particle of rapamycin and carrier protein (being also referred to as " Nanoparticulate compositions ") demonstrates significantly and to suppress the being implanted into growth (embodiment 3) of the human breast carcinoma knurl in the mouse model and to be suppressed at tumor growth (embodiment 12B) in the mouse with MM1S Huppert's disease tumor xenogeneic graft. This nanoparticle formulations that contains albuminous rapamycin is nontoxic under test dose and demonstrates linear pharmacokinetics (embodiment 2) with respect to dosage. The Albumin receptor (gp60) of the nanoparticle formulations of albumin and rapamycin by the SPARC albumen-combination of mediation strengthens tumour and penetrates (tumorpenetration), and SPARC albumen (for example breast cancer cell) in some cancer cells is raised. The Nab-rapamycin specificity of this enhancing can increase the validity and the rapamycin that can allow to use than low dosage of rapamycin, and this can minimize the toxic action of rapamycin, and still suppresses, stablizes, prevents or postpone tumor growth. The specificity that strengthens also can reduce the toxic and side effect from rapamycin and non-cancer cell and tissue interaction, and for example sometimes restriction can be given the intestines toxicity of patient's rapamycin dosage. The nanoparticle formulations of rapamycin has also increased the dissolubility of rapamycin, and if expectation, allow to use bigger dosage.

Definition

As using at this paper, " composition " or " multiple combination thing " comprises and suitable composition of the present invention. The present invention also provides the pharmaceutical composition that is included in composition described herein.

Therefore refer to rapamycin or its derivative at this paper term " rapamycin ", and the present invention considers and comprises all these embodiments. Rapamycin is sometimes referred to as sirolimus (sirolimus), rapammune (rapammune) or rapammune (rapamune) elsewhere. The quoting that intention is simplified this specification and be exemplary of " rapamycin ". The derivative of rapamycin includes, but are not limited to the compound that structure is similar to rapamycin, perhaps with the same total chemical classes of the pharmaceutically-acceptable salts of rapamycin, forms of rapamycin analogs or rapamycin or derivatives thereof or analog in compound. In some embodiments, the rapamycin or derivatives thereof increases basic AKT (basal AKT) activity, increase the AKT phosphorylation, increase the PI3-kinase activity, increased the length (activation of for example inducing by external source IGF-1) of AKT activation, the serine phosphorylation that suppresses IRS-1, suppress the IRS-1 degraded, suppress or change CXCR4 Subcellular Localization, suppress the VEGF secretion, reduce the expression of Cyclin D2, reduce the expression of survivin, suppress the multiple myeloma cells growth that IL-6-induces, inhibition cancer cell propagation, increase Apoptosis, increase cell cycle arrest, increase the division of poly-(ADP ribose) polymerase, increase the division of caspase-8/ Caspase-9, the signal conduction of change or inhibition of phosphatidylinositol3 3-kinase/AKT/mTOR and/or cyclin D1/retinoblastoma approach, suppress the blood vessel generation and/or suppress osteoclast formation. In some embodiments, the derivative of rapamycin keeps and similar one or more biologies of rapamycin, pharmacology, chemistry and/or physical property (comprising for example functional). In some embodiments, rapamycin derivative have at least the rapamycin activity about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% any. The minimizing of the tumor size that for example, is caused by rapamycin derivative, cancer cell quantity or tumor growth rate preferably be at least the corresponding minimizing that causes of the rapamycin by equal number about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% any. Exemplary rapamycin derivative comprises the benzoyl rapamycin, and as disclosed in WO 2006/089207 [0022] section, it all is incorporated herein by reference with it at this. Other exemplary rapamycin derivative comprises WY-090217, AY-22989, NSC-226080, SiiA-9268A, oxa-azepine three hendecenes (oxaazacyclohentriacontine), CCI-779 (CCI 779 (Wyeth)), everolimus (RAD 001 (Novartis)), Elidel (ASM981), SDZ-RAD, SAR943, ABT-578, AP23573 and biological Li Mosi (Biolimus) A9.

Point out that unless have clearly in addition " individuality " that use in this article is mammal, includes but not limited to primate, people, ox, horse, cats, canid or rodent.

As using at this paper, " treatment " or " processing " is the method that obtains to comprise the useful or required result of clinical effectiveness. For the object of the invention, useful or required clinical effectiveness includes but not limited to following arbitrary or a plurality of: reduce one or more symptoms of being produced by disease, degree palliates a disease, stable disease (for example preventing or postponed the deterioration of disease), prevention or delay disease are sent out (for example, shifting), prevention or delay disease take place or recurrence, postpone or the PD that slows down, improve morbid state, the mitigation (no matter being part or all of) of disease is provided, reduce the dosage of the essential other medicines of one or more treatment diseases, postpone PD, increase quality of life and/or prolong existence. In some embodiments, compare or compare with the corresponding symptom among other subject who does not accept composition with the corresponding symptom among the identical subject before treatment, composition has reduced the seriousness of one or more symptoms relevant with cancer, is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% any. " treatment " comprises that also the pathological consequences of cancer alleviates. The inventive method has been considered arbitrary or multiple in these treatment aspects.

As using at this paper, the development of " delay " cancer mean delay, hinder, slow down, slow down, stable and/or postpone advancing of disease. This delay can have the time of variation length, and this depends on the historical of disease and/or the individuality of being treated. That significantly on effect, enough or significant delay can comprise prevention, because individuality does not develop disease for those skilled in the art. When not using the method to compare, the method for " delay " cancer development is that (a given time frame) reduces the possibility of disease progression and/or reduce in the specified period disease degree in the specified period. This more generally according to the clinical research result, the subject of significance quantity on the use statistics. The physical examination of Application standard method such as routine, mammography, imaging or biopsy can detect cancer development. Development also can refer to the beginning undetected PD of possibility and comprise generation, recurrence and outbreak.

As using at this paper, " adventurous " individuality is the individuality that is in the developing cancer danger. " adventurous " is individual can be suffered from or can not suffer from detectable disease and can show or can not show detectable disease before methods for the treatment of described herein. " adventurous " expression individuality has one or more so-called risk factors, and risk factor is the measurable parameter relevant with cancer development, and it is described in this article. There is the individuality ratio of one or more these risk factors not have the individuality of these risk factors (one or more) to have the possibility of higher developing cancer.

" auxiliary situation (adjuvant setting) " refer to wherein individuality had the cancer medical history and usually (but not being inevitably) treatment is had the clinical scenarios of replying, described treatment includes but not limited to operation (such as excision), radiation and chemotherapy. Yet because these individualities have the medical history of cancer, so they considered to be in the risk of development disease. Treatment in " auxiliary situation " or administration refer to therapeutic modality subsequently. Degree of danger (that is, when the individuality in the auxiliary situation is considered to " excessive risk " or " low-risk ") depends on several factors, is generally the disease degree when treating first most.

" newly auxiliary situation (neoadjuvant setting) " refers in preliminary/conclusive treatment (primary/definitive therapy) effective clinical scenarios of method before.

The compound that as employed at this paper, " pharmaceutically active compound " means and induce desired effects---for example treat, stablize, prevent and/or postpone cancer---.

As used herein, " conjoint therapy " means that first therapy that comprises the nano particle that comprises rapamycin or derivatives thereof and carrier protein and second therapy that can be used for treating, stablize, prevent and/or postpone cancer (for example radiate, operation or chemotherapeutics) unite. Be included in same composition or the different components (multiple) in succession with another kind of compound " associating " administration, simultaneously or continuously administration. In some variants, conjoint therapy randomly comprises one or more pharmaceutically acceptable carriers or excipient, non-pharmaceutically active compound and/or inert substance.

Term " effective dose " meaning is composition (nano particle that for example contains rapamycin or derivatives thereof and carrier protein), first therapy, second therapy or the such amount of conjoint therapy, according to specialist's knowledge of operation, in specific therapy form, should be effective in conjunction with its effectiveness and toxicity parameter. In various embodiments, the composition of effective dose or therapy can: (i) reduce cancer cell quantity; (ii) reduce tumor size; (iii) suppress to a certain extent, postpone, slow down, and preferably stop cancer cell and infiltrate to the peripheral organ; (iv) suppress (for example, slow down to a certain extent, preferably stop) metastases; (v) suppress tumor growth; (vi) prevent or postpone that tumour takes place and/or recurrence; And/or (vii) alleviate to a certain extent and one or more of the symptom of related to cancer. In various embodiments, this amount is enough to improve, alleviate, alleviate and/or postpone one or more symptoms of cancer.

In some embodiments, with corresponding tumor size, cancer cell quantity among the identical subject before treatment tumor growth rate is compared or the identical subject that do not receiving treatment in corresponding activity compare, the amount of composition, first therapy, second therapy or conjoint therapy is to be enough to reduce tumor size, to reduce cancer cell quantity or to reduce in the tumor growth rate at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% any amount. The method of standard can be used for measuring the size of this effect, as with the external test of purifying enzyme, mensuration, animal model or people's test based on cell.

As understanding this area, " effective dose " can be with one or more dosage, that is, single dose or a plurality of dosage may be that to obtain the treatment terminal point wanted necessary. Effective dose can be considered in one or more therapeutic agent situations giving, if and with one or more other medicaments associating, Nanoparticulate compositions (composition that for example comprises rapamycin and carrier protein) can be considered to give with effective dose, can obtain or result that obtain to expect or useful. Component in conjoint therapy of the present invention (for example, first and second therapies) can be in succession, simultaneously or give continuously, every kind of component is used identical or different administration path. Therefore, the therapeutic alliance of effective dose comprises when in succession, simultaneously or produced the result's who wants the amount of first therapy and the amount of second therapy when giving continuously.

The amount that " treatment effective dose " refers to composition (nano particle that for example, contains rapamycin or derivatives thereof and carrier protein), first therapy, second therapy or conjoint therapy be enough to produce the treatment results wanted (for example reduce one or more symptoms of cancer seriousness or duration, stablize cancer one or more symptoms seriousness or eliminated one or more symptoms of cancer). For the purposes for the treatment of, result favourable or that want comprise one or more symptoms of for example reducing by disease---comprising its complication and middle the Pathology that is occurring during the disease progression---generation (on biochemical, the histology and/or behavior aspect), improve quality of life, the dosage that reduces the required other medicines for the treatment of disease, the effect that strengthens another medicine that suffer Disease, postpone the progress of disease and/or prolongation patient's existence.

" prophylactic effective dose " refers to, when be easy to infect the individual of cancer and/or can developing cancer individual the time, the amount of composition (nano particle that for example contains rapamycin or derivatives thereof and carrier protein), first therapy, second therapy or conjoint therapy is enough to prevent or reduce the seriousness of one or more following symptoms of cancer. For prophylactic purposes, result useful or that want comprises following result, for example eliminates or reduces dangerous, as to alleviate disease in the future seriousness or postpone seizure of disease (for example postponing on the biochemistry, histology of disease and/or the symptom of behavior aspect, its complication and the middle Pathology that occurs) during the future development of disease.

As used herein, it is that first therapy and second therapy in conjoint therapy gave no more than about 15 minutes of the time interval that term " gives " meaning simultaneously, for example in no more than about 10,5 or 1 minutes any. When first and second therapies give simultaneously, first and second therapies can be included in the same composition (composition that has for example comprised the first and second two kinds of therapies) or in the composition that separates (for example, first therapy is in a kind of composition, and second therapy is included in another composition).

As employed at this paper, it is that first therapy and second therapy in conjoint therapy giving more than about 15 minutes interval that term " gives " meaning in succession, for example more than about 20,30,40,50,60 or more minutes random time.Can at first give first therapy or second therapy.First and second therapies are included in the compositions separately, and they can be included in same or the different packing or test kit.

Term " protein " refers to the polymer of amino acid (comprising total length or fragment) of polypeptide or any length, and protein can be linear or branched, comprises the aminoacid of modification and/or is interrupted by non-aminoacid.This term also comprises natural or gets involved the amino acid polymer of modifying, comprises for example disulfide bond formation, glycosylation, fatization, acetylation, phosphorylation or any other operation or modification.Also comprise the polypeptide that for example contains one or more amino acid analogues (for example comprise alpha-non-natural amino acid etc.) in this term the inside, and other modification that is known in the art.At albumen described herein can be natural appearance---just come from or obtain from natural source (for example blood), perhaps synthetic (for example, chemosynthesis, or synthetic by recombinant DNA technology).The carrier protein of example is described at this paper.

Refer to and to suppress the medicament of (for example postpone, minimizing, slack-off and/or prevention) one or more microbial growths at term used herein " antimicrobial ".Significant growth of microorganism can be measured or indicates by the multiple mode that is known in the art, Yi Xia one or more for example: (i) when compositions is administered to individuality, the growth of microorganism in the compositions causes that enough one or more are to individual deleterious effects; (ii) extraneous contamination (for example is exposed to 10-10 under the temperature in 20 to 25 ℃ of scopes ³Individual colony-forming units) after, increases more than about 10 times at growth of microorganism of some time periods (for example 24 hour time period).The indication of other remarkable growth of microorganism is described in the application of U.S.'s sequence number 11/514,030 of application on August 30th, 2006, is incorporated herein it all as a reference.

Include but not limited to monosaccharide, disaccharide, polysaccharide and its derivant or trim at " sugar " used herein.Describe the suitable steamed bun stuffed with sugar of compositions for this paper and draw together for example mannitol, sucrose, fructose, lactose, maltose and trehalose.

As employed at this paper, " pharmaceutically acceptable " or " pharmacology is compatible " meaning is biological or other undesired material, for example do not cause any remarkable undesired biological effect or with compositions in any other composition of comprising not with harmful interactional situation of mode under, this material can be impregnated in the pharmaceutical composition that gives the patient.Pharmaceutically acceptable carrier or excipient preferably satisfy toxicology and production test required standard, and/or are included on the non-active ingredient guide (Inactive Ingredient Guide) of FDA's establishment.

As using at this paper, mention " not being " certain value or parameter mean usually and described " except " certain value or parameter.For example, if what give is not taxane, it means the medicament that gives except taxane.

Mention that at this paper " approximately " certain value or parameter comprise that (and description) relates to the embodiment of this value or parameter itself.For example, the description of mentioning " approximately X " comprises the description to " X ".

As using at this paper with in accessory claim, " (a) " of singulative, " or (or) " and " described (the) " comprise plural indicant, unless in the clear appointment of context alternate manner.Should be appreciated that aspect of the present invention as herein described and embodiment comprise " constituting (consisting) by each side and embodiment " and/or " constituting (consisting essentially of) by each side and embodiment basically ".The treatment method for cancer

The invention provides treatment method for cancer in individual (for example people), this method comprises the compositions that gives individual effective dose, and described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin).The invention provides and treat method for cancer in individual (for example people), this method comprises and gives the compositions that individuality comprises the nano-particle of effective dose that nano-particle comprises rapamycin and albumin.Therapy can be the single current system method or the situation of conjoint therapy.In addition, the invention provides by the following combination that gives individual effective dose and in individuality, treat cancer: a) first therapy, it comprises compositions, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and b) the second useful therapy of treatment cancer.In some embodiments, second therapy comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy and/or chemotherapy (for example, to one or more useful chemical compounds of treatment cancer).It should be understood that the following treatment method for cancer of mentioning and describing is exemplary, and this description is suitable for equally and comprises and use conjoint therapy treatment method for cancer.

Include but not limited to adrenocortical carcinoma (adenocortical carcinoma) by the treatable cancer example of method of the present invention, agnogenic myeloid metaplasia, the cancer that AIDS is relevant (for example relevant lymphoma of AIDS), anus cancer, the vermiform appendix cancer, astrocytoma (for example cerebellum with brain), basal cell carcinoma, cancer of biliary duct (for example liver outer), bladder cancer, osteocarcinoma (osteosarcoma and malignant fibrohistiocytoma), the cerebral tumor (glioma for example, the brain stem glioma, cerebellum or big cerebral astrocytoma (for example pilocytic astrocytoma, the diffusivity astrocytoma, anaplastic (pernicious) astrocytoma), glioblastoma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, original on the curtain (supratentorial primitive) neuroectodermal tumors, pathways for vision and hypothalamus glioma and glioblastoma), breast carcinoma, bronchial adenoma/carcinoid tumor, carcinoid tumor (for example gastrointestinal carcinoid tumor), unknown elementary cancer, central nervous system lymphoma, cervical cancer, colon cancer, colorectal carcinoma, chronic myeloproliferative disease, carcinoma of endometrium (for example uterus carcinoma), ependymoma, the esophageal carcinoma, Juventus tumor family, cancer eye (for example intraocular melanoma and retinoblastoma), carcinoma of gallbladder, stomach (stomach) cancer, the gastrointestinal associated cancers tumor, gastrointestinal stromal tumor (GIST), the sexual cell carcinoma is (for example outside the cranium, outside the gonad, ovary), the gestation trophoblastic tumor, head and neck cancer, hepatocyte (liver) cancer (for example hepatocarcinoma tumor and hepatocarcinoma), hypopharyngeal cancer, islet-cell carcinoma (endocrine pancreas), laryngeal carcinoma, laryngeal carcinoma, leukemia, lip and oral cancer, oral cancer, hepatocarcinoma, pulmonary carcinoma (small cell lung cancer, nonsmall-cell lung cancer, adenocarcinoma of lung and squamous cell lung carcinoma), lymph vegetation (for example lymphoma), medulloblastoma, melanoma, mesothelioma, transitivity neck squamous cell cancer, oral cancer, multiple endocrine neoplasia syndrome, myelodysplastic syndrome, myeloproliferative disorder/myeloproliferative disease, nasal cavity and nasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, neuroendocrine carcinoma, the oropharynx cancer, ovarian cancer (epithelial ovarian cancer for example, the ovarian germ cell carcinoma, ovary hangs down pernicious potential tumor (potential tumor)), cancer of pancreas, parathyroid carcinoma, carcinoma of penis, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pineocytoma and curtain are gone up original neuroectodermal tumors, pituitary tumor, pleuropulmonary blastoma, lymphoma, primary central nervous system lymphoma (microglioma), PLM, rectal cancer, renal carcinoma, renal pelvis and carcinoma of ureter (transition cell cancer), rhabdomyosarcoma, the glandula cancer, skin carcinoma (for example non-melanoma (for example squamous cell carcinoma), melanoma and Merkel cell cancer), carcinoma of small intestine, squamous cell cancer, carcinoma of testis, laryngocarcinoma, thymoma and thymic carcinoma, thyroid carcinoma, tuberous sclerosis, carcinoma of urethra, cancer of vagina, carcinoma vulvae, wilms tumor and transplanting back lymphadenosis disorder (PTLD), the abnormal angiogenesis relevant with phakomatoses, edema (for example relevant edema) and Meigs syndrome with cerebroma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is lymph vegetation (a for example lymphoma).In some embodiments, provide by the compositions that gives effective dose and treated method for cancer in the individuality to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is lymph vegetation (a for example lymphoma).

In some embodiments, lymph vegetation (for example lymphoma) is B-cell vegetation.The excrescent example of B-cell includes but not limited to precursor B-cell vegetation (for example precursor B-lymphoblast leukemia/lymphoma) and periphery B-cell vegetation (B-cell chronic lymphocytic leukemia/prolymphocytic leukemia/small lymphocyte lymphoma (small lymphocyte (SL) NHL) for example, lymph-plasma cell sample lymphoma/immunocytoma, lymphoma mantle cell, folliculus center lymphoma, follicular lymphoma (cytology's grade: I (minicell) for example, II (blended minicell and maxicell), III (maxicell) and/or hypotype: diffusivity and minicell type mainly), low level/folliculus non-Hodgkin lymphoma (NHL), middle rank/folliculus NHL, marginal zone B-cell lymphoma (for example knot outer (for example the MALT-type+/-mononuclear cell sample B cell) and/or joint (for example+/-mononuclear cell sample B cell)), the splenic marginal zone lymphoma (for example+/-the fine hair lymphocyte), hairy cell leukemia, plasmocytoma/plasma cell myeloma (for example myeloma and multiple myeloma), diffuse large B-cell lymphoma (for example Primary Mediastinal (thymus) B-cell lymphoma), middle rank diffusivity NHL, Burkitt lymphoma, high malignancy B-cell lymphoma, the Hugh Burkitt sample, high malignancy immunoblast NHL, high malignancy lymphoblast NHL, the small-sized no lacunar cell NHL of high malignancy (high grade smallnoncleaved cell NHL), the lump sexually transmitted disease (STD) becomes NHL, relevant lymphoma of AIDS and macroglobulinemia Waldenstron).

In some embodiments, lymph vegetation (for example lymphoma) is the T-cell and/or the NK-cell vegetation of inferring.T-cell and/or the excrescent example of NK-cell of inferring include but not limited to precursor T-cell vegetation (precursor T-lymphoblast lymphoma/leukemia) and peripheral t-cell and NK-cell vegetation (for example T-cell chronic lymphocytic leukemia/prolymphocytic leukemia and large granular lymphocyte leukemia (LGL) (for example T-cellular type and/or NK-cellular type), skin T-cell lymphoma (for example mycosis fungoides (Mycosisfungoids)/Sezary syndrome), non-specific constitutional T-cell lymphoma (cytology's classification (for example medium sized cell for example, blended medium cell and maxicell), maxicell, the lymphocytic epithelium cell, hypotype liver spleen gamma delta T-cell lymphoma and subcutaneous panniculitis (panniculitic) T-cell lymphoma), blood vessel immunoblast T-cell lymphoma (AILD), the blood vessel center lymphoma, Intestinal T-cell lymphoma (for example+/-enteropathy is relevant, Adult T-cell lymphoma/leukemia (ATL), primary cutaneous type (ALCL) (CD30+ for example, T-and null cell type), primary cutaneous type and Huo Qijin sample).

In some embodiments, lymph sample vegetation (for example lymphoma) is Hodgkin.For example, Hodgkin can be lymphocytic predominance, nodular sclerosis, mixed cell type, LD and/or lymphocyte concentration type.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a leukemia.In some embodiments, provide the method that arrives individual (for example people) treatment individual cancer by the compositions that gives effective dose, described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a leukemia.In some embodiments, leukemia is a chronic leukemia.The example of chronic leukemia includes but not limited to chronic myeloid I (granulocytic) leukemia, chronic bone marrow and chronic lymphocytic leukemia (CLL).In some embodiments, leukemia is acute leukemia.The example of acute leukemia includes but not limited to acute lymphoblastic leukemia (ALL), acute myeloid leukemia, acute lymphoblastic leukemia and acute myeloid leukemia (for example myeloblast, promyelocyte, myelomonocyte, mononuclear cell and erythrocyte leucocythemia).

In some embodiments, provide with the combination treatment method for cancer that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), wherein cancer is aqueous tumor (liquid tumor) or plasmocytoma.In some embodiments, provide the method that arrives individual (for example people) treatment individual cancer by the compositions that gives effective dose, described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is aqueous tumor or plasmocytoma.Plasmocytoma includes but not limited to myeloma.Myeloma includes but not limited to extramedullary plasmacytoma, solitary myeloma and multiple myeloma.In some embodiments, plasmocytoma is multiple myeloma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a multiple myeloma.In some embodiments, provide the method that arrives individual (for example people) treatment individual cancer by the compositions that gives effective dose, described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a multiple myeloma.The example of multiple myeloma includes but not limited to IgG multiple myeloma, IgA multiple myeloma, IgD multiple myeloma, IgE multiple myeloma and non-secretory multiple myeloma.In some embodiments, multiple myeloma is the IgG multiple myeloma.In some embodiments, multiple myeloma is the IgA multiple myeloma.In some embodiments, multiple myeloma is to glow (smoldering) or painless property multiple myeloma.In some embodiments, multiple myeloma is carrying out a property multiple myeloma.In some embodiments, what multiple myeloma can be to drug resistant, medicine is such as but not limited to bortezomib (bortezomib), dexamethasone (Dex-), amycin (Dox-) and melphalan (LR).

In some embodiments, individuality can be the people with the gene relevant with multiple myeloma, genetic mutation or polymorphism (polymorphism) (for example ras, PTEN, Rb1, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B and/or p53), or has the people of the additional copy of one or more genes relevant with multiple myeloma.In some embodiments, individuality has ras or PTEN sudden change.In some embodiments, cancerous cell relies on the mTOR approach and translates one or more mRNA.In some embodiments, cancerous cell can not synthesize mRNAs by mTOR-dependent/non-dependent approach.In some embodiments, compare with non-cancerous cell, cancerous cell has reduced or has not had the PTEN activity, or has reduced or do not had the expression of PTEN.In some embodiments, compare with non-cancerous cell, cancerous cell has increased the active and/or expression of AKT.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a solid tumor.In some embodiments, provide the method that arrives individual (for example people) treatment individual cancer by the compositions that gives effective dose, described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a solid tumor.In some embodiments, solid tumor includes but not limited to sarcoma and cancer, for example fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, Kaposi sarcoma, soft tissue sarcoma, uterus synovial sarcoma (uterine sacronomasynovioma), mesothelioma, the You Wenshi tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, cancer of pancreas, breast carcinoma, ovarian cancer, carcinoma of prostate, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, syringocarcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocarcinoma, cancer of biliary duct, choriocarcinoma, spermocytoma, embryoma, nephroblastoma, cervical cancer, tumor of testis, pulmonary carcinoma, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma (menangioma), melanoma, neuroblastoma and retinoblastoma.

Therefore, in some embodiments, the method that arrives individual (for example people) treatment individual cancer by the compositions that gives effective dose is provided, and described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a breast carcinoma.In some embodiments, provide the method that arrives breast carcinoma in individual (for example people) treatment individuality by the compositions that gives effective dose, described compositions comprises and contains rapamycin or derivatives thereof and albuminous nano-particle.In some embodiments, breast carcinoma is breast carcinoma of early stage, non-metastatic breast carcinoma, advanced breast cancer, IV primary breast cancer, local advanced breast cancer, metastatic breast cancer, catabasis breast carcinoma, auxiliary situation breast carcinoma or newly auxiliary situation breast carcinoma.In some specific implementations, breast carcinoma is to be in new auxiliary situation.The method of treatment terminal cancer (one or more) is provided in some embodiments.In some embodiments, provide the method (breast carcinoma can be the HER2 positive or HER2 feminine gender) of treatment breast carcinoma, breast carcinoma comprises for example advanced breast cancer, IV primary breast cancer, local advanced breast cancer and metastatic breast cancer.In some embodiments, individuality can be the people with the gene relevant with breast carcinoma, genetic mutation or polymorphism (for example BRCA1, BRCA2, ATM, CHEK2, RAD51, AR, DIRAS3, ERBB2, TP53, AKT, PTEN and/or PI3K), or has the people of the additional copy (additional copies of for example one or more HER2 genes) of one or more genes relevant with breast carcinoma.In some embodiments, this method also comprises according to the hormone receptor situation identification cancer patient crowd (for example breast carcinoma crowd) of the patient with the tumor tissues of not expressing ER and PgR and gives to contain comprising of this patient crowd's effective dose the compositions of the nano-particle of rapamycin or derivatives thereof and carrier protein (for example albumin).

In some embodiments, provide by the compositions that gives effective dose and treat method for cancer in the individuality to individual (for example people), described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is renal cell carcinoma (being also referred to as renal carcinoma, renal adenocarcinoma or hypernephroma).In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains albuminous nano-particle, and wherein cancer is a renal cell carcinoma.In some embodiments, renal cell carcinoma is an adenocarcinoma.In some embodiments, renal cell carcinoma is clear cell renal cell carcinoma, Papillary Renal Cell Carcinoma (be also referred to as to have a liking for and dye renal cell carcinoma), chromophobe cell renal cell carcinoma, collecting pipe renal cell carcinoma, cirrhosis of kidney cell carcinoma, mixes granular renal cell carcinoma, kidney angiomyoliopma or spindle renal cell carcinoma.In some embodiments, individuality can be the people with the gene relevant with renal cell carcinoma, genetic mutation or polymorphism (for example VHL, TSC1, TSC2, CUL2, MSH2, MLH1, INK4a/ARF, MET, TGF-α, TGF-β 1, IGF1, IGF-1R, AKT and/or PTEN), or has the people of the additional copy of one or more genes relevant with renal cell carcinoma.In some embodiments, renal cell carcinoma is with following relevant: (1) Feng Xi-Lin Er Shi (VHL) syndrome, (2) heritability mastoid process sample renal carcinoma (HPRC), (3) crow with ripple-Hao Ge-the Doby syndrome (Birt-Hogg-Dube syndrome (BHDS)) relevant familial renal oncocytoma (FRO) or (4) heritability renal carcinoma (HRC).Provide treatment to be in any method of renal cell carcinoma of I, II, III or the IV fourth phase according to AJCCS (AJCC).In some embodiments, renal cell carcinoma is an IV phase renal cell carcinoma.

In some embodiments, provide by the compositions that gives effective dose and treat method for cancer in the individuality to individual (for example people), described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a carcinoma of prostate.In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a carcinoma of prostate.In some embodiments, carcinoma of prostate is an adenocarcinoma.In some embodiments, carcinoma of prostate is sarcoma, neuroendocrine tumour, small cell carcinoma, duct carcinoma or lymphoma.Provide treatment according to Jewett by stages system be in the method for A, B, C or D carcinoma of prostate of arbitrary phase in the fourth phase.In some embodiments, carcinoma of prostate is A phase carcinoma of prostate (can not feel during examination per rectum cancer).In some embodiments, carcinoma of prostate is B phase carcinoma of prostate (tumor relates to intraprostatic a plurality of tissue, and it can be felt during examination per rectum, and perhaps it is found with biopsy, and carrying out biopsy is because high PSA level).In some embodiments, carcinoma of prostate is C phase carcinoma of prostate (cancer has been diffused into prostate outward near tissue).In some embodiments, carcinoma of prostate is a D phase carcinoma of prostate.In some embodiments, carcinoma of prostate can be androgen independent prostate cancer (AIPC).In some embodiments, carcinoma of prostate can be an androgen dependent prostate cancer.In some embodiments, carcinoma of prostate is can hormonotherapy refractory.In some embodiments, carcinoma of prostate can be that hormonotherapy is refractory substantially.In some embodiments, individuality can be the people with the gene relevant with carcinoma of prostate, genetic mutation or polymorphism (for example RNASEL/HPC1, ELAC2/HPC2, SR-A/MSR1, CHEK2, BRCA2, PON1, OGG1, MIC-1, TLR4 and/or PTEN), or has the people of the additional copy of one or more genes relevant with carcinoma of prostate.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a pulmonary carcinoma.In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a pulmonary carcinoma.In some embodiments, the pulmonary carcinoma of cancer right and wrong-small cell lung cancer (NSCLC).The example of NCSLC includes but not limited to large cell carcinoma (maxicell neuroendocrine carcinoma for example, compound maxicell neuroendocrine carcinoma, basaloid carcinoma, lymphepithelioma sample cancer, clear cell carcinoma and large cell carcinoma) with clava phenotype, adenocarcinoma (acinus type for example, mamillary (bronchioloalveolar carcinoma for example, non-mucus, mucus, mucus and non-mucus mix and indefinite cellular type), the entity mucinous adenocarcinoma, mix hypotype adenocarcinoma, WD fetus adenocarcinoma, mucus (colloid) adenocarcinoma, mucous cystoadenocarcinoma, ring bodies adenocarcinoma and clear cell adenocarcinoma), neuroendocrine lung tumor and squamous cell carcinoma (mamillary for example, clear cell, minicell and basal cell sample).In some embodiments, NSCLC can be T phase tumor (primary tumor), N phase tumor (regional nodes) or the M phase tumor (far-end transfer) according to the TNM classification.In some embodiments, pulmonary carcinoma is carcinoid tumor (typical or atypical), adenosquamous carcinoma, cylindroma or glandula cancer (for example adenoid cystic carcinoma or mucoepidermoid carcinoma).In some embodiments, pulmonary carcinoma is the cancer (for example, having spindle and/or cytomegalic cancer, spindle cell cancer, carcinoma gigantocellulare, carcinosarcoma or pulmonary blastoma) with pleomorphism (pleomorphic), sarcoma sample or sarcoma composition.In some embodiments, cancer is small cell lung cancer (SCLC; Be also referred to as oat-cell carcinoma).Small cell lung cancer can be restricted period (limited-stage), diffusion period or recurrent small cell lung cancer.In some embodiments, individuality can be to have suspection or demonstration gene, genetic mutation or the polymorphism relevant with pulmonary carcinoma (for example SASH1, LATS1, IGF2R, PARK2, KRAS, PTEN, Kras2, Krag, Pas1, ERCC1, XPD, IL8RA, EGFR, α ₁-AD, EPHX, MMP1, MMP2, MMP3, MMP12, IL1 β, RAS and/or AKT) the people, or have the people of the additional copy of one or more genes relevant with pulmonary carcinoma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is the brain cancer.In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is the brain cancer.In some embodiments, the brain cancer is original neuroectodermal tumors on the astrocytoma (for example astrocytoma pilocytic, fill the air astrocytoma or anaplastic (pernicious) astrocytoma), glioblastoma, ependymoma, oligodendroglioma, meningioma, craniopharyngioma, hemangioblastoma, medulloblastoma, curtain of glioma, brain stem glioma, cerebellum or brain, pathways for vision and hypothalamus glioma or glioblastoma.In some embodiments, the brain cancer is glioblastoma (being also referred to as multiform glioblastoma or 4 grades of astrocytomas).In some embodiments, glioblastoma is the radiation resistance.In some embodiments, glioblastoma is a radiosensitivity.In some embodiments, glioblastoma can be under the curtain.In some embodiments, glioblastoma is on the curtain.In some embodiments, individuality can be the people with gene, genetic mutation or the polymorphism relevant with the brain cancer (for example glioblastoma) (for example NRP/B, MAGE-E1, MMACI-E1, PTEN, LOH, p53, MDM2, DCC, TP-73, Rb1, EGFR, PDGFR-α, PMS2, MLH1 and/or DMBT1), or has the people of the additional copy (for example MDM2, EGFR and PDGR-α) of one or more genes relevant with the brain cancer (for example glioblastoma).

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a melanoma.In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is a melanoma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is an ovarian cancer.In some embodiments, provide by the compositions that gives effective dose and treat method for cancer to individual (for example people), described compositions comprises and contains rapamycin and albuminous nano-particle, and wherein cancer is an ovarian cancer.In some embodiments, cancer is an epithelial ovarian cancer.Exemplary epithelial ovarian cancer histologic classification comprises: serous cystoma (for example optimum serous cystadenoma, have epithelial cell proliferation activity and dyskaryosis, but the serous cystadenoma that does not have the seepage failure growth, or serous cystadenocarcinoma), myxoid cystoma (the optimum cystadenoma of mucus for example, have epithelial cell proliferation activity and dyskaryosis, but the mucinous cystadenoma that does not have the seepage failure growth, or mucous cystoadenocarcinoma), clear cell (middle kidney sample) tumor (for example optimum clear cell tumor, have epithelial cell proliferation activity and dyskaryosis, but the clear cell tumor that does not have the seepage failure growth, or clear cell cystadenocarcinoma), unfiled tumor or other malignant tumor that one of can not be included in above-mentioned group.In various embodiments, epithelial ovarian cancer is I phase (for example IA, IB or IC phase), II phase (for example IIA, IIB or IIC phase), III phase (for example IIIA, IIIB or IIIC phase) or IV phase.In some embodiments, individuality can be the people with the gene relevant with ovarian cancer, genetic mutation or polymorphism (for example BRCA1 or BRCA2), or has the people of the additional copy (for example one or more additional copies of HER2 gene) of one or more genes relevant with ovarian cancer.

In some embodiments, cancer is an ovarian germ cell tumors.The example organization hypotype comprises dysgerminoma or other sexual cell tumor (for example, endodermal sinus tumor such as liver sample or intestinal neoplasms, embryonal carcinoma, germinoma (olyembryomas), choriocarcinoma, teratoma or mixed type tumor).Exemplary teratoma is immature teratoma, mature teratoma, solid teratoma and cystic teratoma (dermoid cyst for example, as dermoid cyst and have the dermoid cyst of vicious transformation).Some teratomas be monolayer with high degree of specificity, for example struma ovarii, carcinoid tumor, struma ovarii and carcinoid tumor or other (for example pernicious neuroderm and ependymoma).In some embodiments, ovarian germ cell tumors is I phase (for example IA, IB or IC phase), II phase (for example IIA, IIB or IIC phase), III phase (for example IIIA, IIIB or IIIC phase) or IV phase.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a neuroendocrine carcinoma.In some embodiments, individuality can be the people with the gene relevant with neuroendocrine carcinoma, genetic mutation or polymorphism (for example TSC1, TSC2, IGF-1, IGF-1R and/or VHL), or has the people of the additional copy of one or more genes relevant with neuroendocrine carcinoma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is a colon cancer.In some embodiments, individuality can be the people with the gene relevant with colon cancer, genetic mutation or polymorphism (for example RAS, AKT, PTEN, PI3K and/or EGFR), or has the people of the additional copy of one or more genes relevant with colon cancer.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is that to activate with PI3K and/or AKT be feature.In some embodiments, activating with PI3K and/or AKT is that the cancer of feature is HER2 ⁺Breast carcinoma, chronic lymphocytic leukemia, ovarian cancer, carcinoma of endometrium, sarcoma, head and neck squamous cell carcinoma or thyroid carcinoma.In some embodiments, cancer is a feature with AKT gene amplification also.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to be feature with the cyclin D1 overexpression.In some embodiments, be that the cancer of feature is lymphoma mantle cell or breast carcinoma with the cyclin D1 overexpression.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to be feature with the cMYC overexpression.In some embodiments, be that the cancer of feature is a Burkitt lymphoma with the cMYC overexpression.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to be feature with the HIF overexpression.In some embodiments, be that the cancer of feature is renal cell carcinoma or Von Hippel-Lindau disease (von hippel-lindau) with the HIF overexpression.In some embodiments, cancer also comprises the VHL sudden change.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to be feature with TSC1 and/or TSC2 forfeiture.In some embodiments, be that the cancer of feature is tuberous sclerosis or PLM with TSC1 and/or TSC2 forfeiture.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to sport feature with TSC2.In some embodiments, the cancer that sports feature with TSC2 is the kidney angiomyoliopma.

In some embodiments, the method for the treatment of individual cancer by the compositions that gives effective dose to individual (for example people) is provided, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein cancer is to sport feature with PTEN.In some embodiments, the PTEN sudden change is the PTEN afunction.In some embodiments, the cancer that sports feature with PTEN is glioblastoma, carcinoma of endometrium, carcinoma of prostate, sarcoma or breast carcinoma.

In some embodiments, also can be used for the treatment of the cancer that is not solid tumor (that is to say) at Therapeutic Method provided herein except solid tumor.In some embodiments, provide the method for treatment also can be used for the treatment of the cancer that is not carcinoma at this paper.In some embodiments, also can be used for the treatment of the cancer that is not sarcoma at Therapeutic Method provided herein.In some embodiments, also can be used for the treatment of at Therapeutic Method provided herein and be not lymphadenomatous cancer.In some embodiments, also can be used for the treatment of the cancer that is not colon cancer (that is to say) at Therapeutic Method provided herein except colon cancer.In some embodiments, also can be used for the treatment of the cancer that is not breast carcinoma (that is to say) at Therapeutic Method provided herein except breast carcinoma.In some embodiments, also can be used for the treatment of the cancer that is not ovarian cancer, the brain cancer and/or carcinoma of prostate (that is to say) at Therapeutic Method provided herein except ovarian cancer, the brain cancer and/or carcinoma of prostate.

In Therapeutic Method provided herein any can be used for the treatment of primary tumor.In Therapeutic Method provided herein any also can be used for the treatment of metastatic cancer (i.e. the cancer that is shifted by primary tumor).In Therapeutic Method provided herein any can be used for the treatment of terminal cancer.In Therapeutic Method provided herein any can be used for the treatment of local advanced carcinoma.In Therapeutic Method provided herein any can be used for the treatment of the early cancer.In Therapeutic Method provided herein any can be used for the treatment of the catabasis cancer.In some embodiments of in Therapeutic Method provided herein any, cancer is alleviating the back recurrence.In some embodiments of in Therapeutic Method provided herein any, cancer is a progressive carcinoma disease.In Therapeutic Method provided herein any can be used for the treatment of the invalid substantially cancer of hormonotherapy.In Therapeutic Method provided herein any can be used for the treatment of the positive cancer of HER-2.In Therapeutic Method provided herein any can be used for the treatment of the negative cancer of HER-2.

In Therapeutic Method provided herein any can be used for the treatment of after diagnosing or suspect the individuality (for example people) of suffering from cancer.In some embodiments, individuality can be the people who shows one or more symptoms relevant with cancer.In some embodiments, individuality can suffer from the disease of the disease in late period or light degree as low tumor load (low tumorburden).In some embodiments, to be in cancer early stage for individuality.In some embodiments, individuality is in cancer of late stage.In some embodiments of in Therapeutic Method provided herein any, individuality can be the people of heredity or other easy infection (for example risk factor) developing cancer, and individuality can be or not have diagnosis to suffer from the people of cancer.In some embodiments, these risk factors are drawn together but are not limited to existence, heredity (for example heredity) factor and the environmental exposure of age, sex, race, diet, previous medical history, precursor disease.In some embodiments, the individuality in the cancer risk comprises those individualities that those individualities of for example having the relatives that experience this disease and its danger are determined by heredity or biochemical biomarker analysis.

In the method provided herein any can be with auxiliary situation practice.In the method provided herein any can that is to say with new auxiliary situation practice, this method can be at first/and finishes before the definitiveness therapy.In some embodiments, any in the Therapeutic Method provided herein can be used for the treatment of the individuality of before having treated.In the Therapeutic Method provided herein any can be used for the treatment of the individuality that does not before have treatment.In the Therapeutic Method provided herein any can be used for the treatment of in the danger that is in developing cancer, still not have diagnosis to suffer from the individuality of cancer.In the treatment cancer method provided herein any can be used for as a gamma therapy.In the treatment cancer method provided herein any can be used for as two gamma therapies.

In Therapeutic Method provided herein, in any some embodiments, do not give individual taxane.In some embodiments, the taxane that gives is not a Nanoparticulate compositions.In some embodiments, the Nanoparticulate compositions that comprises the rapamycin or derivatives thereof does not give with taxane.In some embodiments, accept at individuality during the Nanoparticulate compositions that comprises the rapamycin or derivatives thereof of one or more dosage, taxane does not give individuality.In some embodiments, before beginning with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individual body and function taxane treatment.For example, before beginning with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individuality can accept one or many days, week, month or year taxane.In other embodiments, before beginning with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individuality is never accepted taxane.In some embodiments, after stopping with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individual body and function taxane treatment.In other embodiments, after stopping with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individuality is never treated with taxane.In some embodiments, compositions, first therapy and/or second therapy do not contain taxane.In other embodiments, compositions, first therapy and/or second therapy comprise taxane.In some embodiments, first and/or second therapy does not comprise SPARC polypeptide or anti-SPARC antibody (that is to say, except SPARC polypeptide or anti--SPARC antibody).

In the Therapeutic Method provided herein any can be used for the treatment of, stablizes, prevents and/or postpone the cancer in any kind or stage.In some embodiments, individuality be at least about 40,45,50,55,60,65,70,75,80 or 85 years old in arbitrary.In some embodiments, improve or eliminated one or more cancer symptoms.In some embodiments, tumor size, cancerous cell quantity or growth of tumor rate are reduced by at least any in about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.In some embodiments, postpone or prevented cancer.Conjoint therapy

This method is also to use conjoint therapy treatment method for cancer to be feature.Therefore, in some embodiments, also give individuality to the second useful therapy of treatment cancer.In some embodiments, second therapy comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy and/or chemotherapy (for example, to useful one or more chemical compounds or its pharmaceutically acceptable salt of treatment cancer).It should be understood that above to treatment cancer method mention and describe to be exemplary, and this descriptions is suitable for equally and comprises that the use conjoint therapy treats method for cancer.

At this on the one hand, the invention provides by the following combination that gives individual effective dose and treat method for cancer in the individuality: a) first therapy, it comprises compositions, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and b) to the second useful therapy of treatment cancer.In some embodiments, second therapy comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy and/or chemotherapy (for example, to one or more useful chemical compounds of treatment cancer).In some embodiments, first and/or second therapy does not comprise taxane.In other embodiments, first and/or second therapy comprises taxane.In some embodiments, first and/or second therapy does not comprise SPARC polypeptide or anti--SPARC antibody.

In some embodiments, the invention provides and treat method for cancer in individuality, it comprises and gives individuality: a) compositions of effective dose, said composition comprise the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin); And b) at least a other chemotherapeutics of effective dose.In some embodiments, nano-particle comprises rapamycin and albumin.In some embodiments, chemotherapeutics be following any (be selected from some embodiments following): antimetabolite (comprising nucleoside analog), based on platinum medicament, alkylating agent, tyrosine kinase inhibitor, anthracycline antibiotics, vinca alkaloids, proteasome inhibitor, taxane, HER2/neu regulator (as the HER2/neu regulator, such as

), the EGFR regulator (as the EGFR regulator, such as ), VEGFR regulator, Farnesyltransferase inhibitor and topology isomerase inhibitors.In some embodiments, chemotherapeutant is not taxane (that is to say that chemical compound is the chemotherapeutics except taxane).Be used for the nano-particle order that comprises rapamycin or derivatives thereof and carrier protein (for example albumin), the preferred agents combination that gives or give simultaneously jointly be those when the time with independent single component comparison, demonstrate the drug regimen of enhanced active anticancer, particularly cause the combination that cancer disappears and/or cancer is cured.

Chemotherapeutics described herein can be medicament self, its pharmaceutically acceptable salt and its pharmaceutically acceptable ester, and stereoisomer, enantiomer, racemic mixture etc.Chemotherapeutics or as the medicament of describing and the pharmaceutical composition that contains medicament (one or more) can be given, wherein said pharmaceutical composition comprises pharmaceutically acceptable vehicle excipients etc.

Chemotherapeutics can exist in Nanoparticulate compositions.For example, in some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) compositions that comprises the nano-particle that contains at least a other chemotherapeutics and carrier protein (for example being albumin) of effective dose.In some embodiments, this method comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) compositions that comprises the nano-particle that contains at least a other chemotherapeutics and carrier protein (for example albumin) of effective dose.In some embodiments, chemotherapeutics be following any (be selected from some embodiments following): muscoril or its derivant (for example dimerization muscoril, it comprises for example Nab-5404, Nab-5800 and Nab-5801); And geldanamycin (geldanamycin) or its derivant (for example amino geldanamycin (17-AAG) of 17-allyl).In some embodiments, chemotherapeutics is taxane or derivatives thereof (for example paclitaxel, Ramulus et folium taxi cuspidatae terpene and ortataxel).In some embodiments, chemotherapeutics is not a taxane.In other embodiments, chemotherapeutant is not a taxane.In some embodiments, chemotherapeutics is 17-AAG.In some embodiments, chemotherapeutics is the dimerization muscoril.

This paper provides the exemplary and nonrestrictive chemotherapeutics inventory of being taken into account.Suitably chemotherapeutics comprises for example vincaleucoblastine, destroy the medicament (as colchicine and its derivant) that microtubule forms, the angiogenesis inhibitor medicine, therapeutic antibodies, the agent of EGFR targeting, tyrosine kinase targeting agent (as tyrosine kinase inhibitor), transient metal complex, proteasome inhibitor, antimetabolite (as nucleoside analog), alkylating agent, medicament based on platinum, anthracycline antibiotics, topoisomerase enzyme inhibitor, therapeutic antibodies, retinoid (as the all-trans-retinoic acid or derivatives thereof); Geldanamycin or derivatives thereof (as 17-AAG) and other standard chemotherapeutics well known in the art.

In some embodiments, chemotherapeutics is a kind of of (being selected from some embodiments) following any material: adriamycin (adriamycin), colchicine, cyclophosphamide, D actinomycin D, bleomycin, daunomycin (duanorubicin), amycin, epirubicin, mitomycin, methotrexate, mitoxantrone, fluorouracil, carboplatin, carmustine (BCNU), Semustine, cisplatin, epotetin alfa, etoposide, interferon (for example IFN-α), camptothecine and derivant thereof, letrozole, handkerchief wood monoclonal antibody (

), phenesterin, hycamtin (topetecan), vinblastine, vincristine, tamoxifen, Thalidomide, for than cut down Buddhist nun (tipifarnib) ( ), piposulfan, Nab-5404, Nab-5800, Nab-5801, Irinotecan, HKP, Ortataxel, gemcitabine, ( ), vinorelbine, hydrochloric acid gentle ratio how

(

), capecitabine,

(

),

(

), ( ),

(

), (

), Lapatinib pool (lapatinib), Sorafenib (Sorafenib), its derivant, chemotherapeutics known in the art and analog.In some embodiments, chemotherapeutics is the compositions that comprises the nano-particle that contains thiocolchicine derivant and carrier protein (for example albumin).In some embodiments, chemotherapeutics is taxane or derivatives thereof (for example paclitaxel, Ramulus et folium taxi cuspidatae terpene and ortataxel).In some embodiments, chemotherapeutant is not a taxane.

In some embodiments, chemotherapeutics is an antineoplastic agent, include but not limited to carboplatin,

(

) (vinorelbine), anthracycline antibiotics (

), Lapatinib (GW57016),

, gemcitabine (

), capecitabine (

),

, cisplatin, 5-fluorouracil, epirubicin, cyclophosphamide,

, etc.

In some embodiments, chemotherapeutics is the antagonist that participates in other factor of tumor growth, the described factor such as EGFR, ErbB2 (being also referred to as Herb), ErbB3, ErbB4 or TNF.Sometimes, it may be useful giving individual one or more cytokines simultaneously.In some embodiments, curative is a growth inhibitor.The suitable dose of growth inhibitor is those amounts of using at present, and can be lowered owing to the synergy (working in coordination with) of growth inhibitor and rapamycin or derivatives thereof.In some embodiments, chemotherapeutics is the chemotherapeutics except anti-VEGF antibodies, HER2 antibody, interferon and HGF beta antagonists.

Mentioning of chemotherapeutics is suitable for described chemotherapeutics or derivatives thereof herein, so the present invention considers and comprises arbitrary these embodiment (medicaments; Medicament or derivant (one or more))." derivant " of chemotherapeutics or other chemical part includes but not limited to, on the structure to this chemotherapeutics or the similar chemical compound of part, the chemical compound that perhaps belongs to same total chemical classes with this chemotherapeutics or part, the analog of this chemotherapeutics, the perhaps pharmaceutically acceptable salt of chemotherapeutics or derivatives thereof.In some embodiments, the derivant of chemotherapeutics or part keeps chemistry and/or the physical property (comprise, for example, functional) similar to this chemotherapeutics or part.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) tyrosine kinase inhibitor of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) tyrosine kinase inhibitor of effective dose.Suitable tyrosine kinase inhibitor for example comprises, imatinib (

), the Buddhist nun rein in for Buddhist nun (nilotinim), gefitinib (

ZD-1839), Te Luokai (

OSI-774), the malic acid Sutent (

), Sorafenib (

) and Lapatinib pool (GW562016; Lapatinib).In some embodiments, tyrosine kinase inhibitor is how reversible (multiplereversible) ErbB1 family tyrosine kinase inhibitor (for example Lapatinib pool).In some embodiments, tyrosine kinase inhibitor list reversible (single reversible) EGFR tyrosine kinase inhibitor (for example gefitinib or Te Luokai).In some embodiments, tyrosine kinase inhibitor is Te Luokai (erlotinib).In some embodiments, tyrosine kinase inhibitor is a gefitinib.In some embodiments, tyrosine kinase inhibitor is single reversible EGFR tyrosine kinase inhibitor (for example EKB-569 or CL-387,785).In some embodiments, tyrosine kinase inhibitor is that (for example how card is for Buddhist nun (CL-1033 for how reversible ErbB family tyrosine kinase inhibitor; PD183805), HKI-272, BIBW2992 or HKI-357).In some embodiments, tyrosine kinase inhibitor is how reversible tyrosine kinase inhibitor (for example ZD-6474, ZD-6464, AEE788 or XL647).In some embodiments, tyrosine kinase inhibitor suppresses ErbB family's allos dimerization effect (for example BMS-599626).In some embodiments, tyrosine kinase inhibitor is by influencing HSP90 Profilin folding (for example benzoquinone, Ansamycin, IPI-504 or 17-AAG).In some embodiments, the method of the EGFR propagation that is suppressed at expressing tumor in the mammal is provided, it comprises that the compositions that gives effective dose and gefitinib are to the mammal that has infected this tumor, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), and wherein gefitinib is given by pulsed administration (pulse-dosing).In some embodiments, tyrosine kinase inhibitor is the inhibitor of BCR-Abl.In some embodiments, tyrosine kinase inhibitor is the inhibitor of IGF-1R.

In some embodiments, method is used for the treatment of non--small cell lung cancer.In some embodiments, method is used for the treatment of the brain cancer (for example glioblastoma).In some embodiments, method is used for the treatment of colorectal carcinoma, gastrointestinal stromal tumors (GISTs), carcinoma of prostate, ovarian cancer or thyroid carcinoma.In some embodiments, method is used for the treatment of carcinoma of prostate (for example advanced prostate cancer).In some embodiments, method is used for the treatment of breast carcinoma, comprises the new auxiliary situation breast carcinoma of treatment metastatic breast cancer and treatment.In some embodiments, method is used for the treatment of advanced solid tumor.In some embodiments, method is used for the treatment of multiple myeloma.In some embodiments, method comprises the while and/or gives at least a EGFR blocker, inhibitor or antagonist in succession.In some embodiments, individuality has active sudden change (one or more) in EGFR kinases territory.In some embodiments, individuality has the ancestors in Asia or East Asia.In some embodiments, individuality is the women.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: the compositions that a) comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) antimetabolite of effective dose (for example nucleoside analog comprises for example purine analogue and pyrimidine analogue).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) antimetabolite of effective dose." antimetabolite (antimetabolic agent) " is structurally similar with metabolite, but the medicament that can not be used by body with effective proved recipe formula.The generation of many antimetabolite interfere RNA, RNA and DNA.For example, antimetabolite can be a nucleoside analog, its include but not limited to azacitidine, azathioprine, capecitabine (

), cytosine arabinoside, cladribine, cytosine arabinoside (cytosine arabinoside) (ara-C, Cytosar), doxifluridine, fluorouracil (as 5-fluorouracil), 9-(2-phosphinylidyne (phosphonyl) methoxyethyl) adenine, UFT, hydroxyurea, gemcitabine, purinethol, methotrexate, thioguanine (as the 6-thioguanine).Other antimetabolite comprises, for example, and altheine enzyme (Elspa), decarbazine (DTIC), 2-deoxy-D-glucose and procarbazine (procarbazine).In some embodiments, nucleoside analog be following in any (with being selected from some embodiments): gemcitabine, fluorouracil and capecitabine.In some embodiments, method is used for the treatment of metastatic breast cancer or local advanced breast cancer.In some embodiments, described method is used for the first-line treatment of metastatic breast cancer.In some embodiments, described method is used for the treatment of the breast carcinoma under the new auxiliary situation.In some embodiments, described method is used for the treatment of any in NSCLC, metastatic colorectal cancer, cancer of pancreas or the advanced solid tumor.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) alkylating agent of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) alkylating agent of effective dose.Suitable alkylating agent includes but not limited to cyclophosphamide (Cytoxan), chlormethine, chlorambucil (chlorambucil), melphalan, carmustine (BCNU), thio-tepa, busulfan, alkylsulfonate, aziridine (ethylene imines), chlormethine analog, estramustine phosphate sodium, ifosfamide (ifosfamide), nitroso ureas, lomustine and streptozocin.In some embodiments, alkylating agent is a cyclophosphamide.In some embodiments, before giving Nanoparticulate compositions, give cyclophosphamide.In some embodiments, described method is used for the treatment of breast carcinoma of early stage.In some embodiments, described method is used for the treatment of the breast carcinoma under auxiliary or newly auxiliary situation.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) medicament based on platinum of effective dose (as carboplatin).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) medicament based on platinum of effective dose (as carboplatin).The suitable medicament based on platinum includes but not limited to carboplatin, cisplatin and oxaliplatin.In some embodiments, the medicament based on platinum is a carboplatin.In some embodiments, the medicament based on platinum is an oxaliplatin.We have observed rapamycin and have suppressed the inductive apoptosis of oxaliplatin in the dose dependent mode.Reach 1: 1 (w/w) ratios of two kinds of medicines by the amount that increases oxaliplatin, this inhibitory action is not submerged.For

(oxaliplatin injection) observed identical situation.

In some embodiments, this method is used for the treatment of breast carcinoma (the HER2 positive or HER2 feminine gender comprise metastatic breast cancer and advanced breast cancer); Pulmonary carcinoma (comprising the malignant solid tumor in late period in advanced NSCLC, a line NSCLC, SCLC and the lung); Ovarian cancer; Head and neck cancer; And melanoma (comprising metastasis melanin tumor).

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) anthracycline antibiotics of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) anthracycline antibiotics of effective dose.How gentle suitable anthracycline antibiotics include but not limited to hydrochloric acid ratio

, D actinomycin D, actinomycin D, daunorubicin (daunomycin), amycin (adriamycin), epirubicin, idarubicin, mitoxantrone and valrubicin.In some embodiments, anthracycline antibiotics be following in any (with being selected from some embodiments): the how gentle ratio of hydrochloric acid

, epirubicin and amycin.In some embodiments, this method is used for the treatment of breast carcinoma of early stage.In some embodiments, this method is used for the treatment of the breast carcinoma under auxiliary or newly auxiliary situation.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) vincaleucoblastine of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) vincaleucoblastine of effective dose.Suitable vincaleucoblastine comprises, for example, vinblastine, vincristine, vindesine, vinorelbine ( ) and VP-16.In some embodiments, vincaleucoblastine be vinorelbine (

).In some embodiments, this method is used for the treatment of IV primary breast cancer and pulmonary carcinoma.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) topoisomerase enzyme inhibitor of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) topoisomerase enzyme inhibitor of effective dose.In some embodiments, chemotherapeutics is a topoisomerase enzyme inhibitor, comprise, for example, the inhibitor of topoisomerase I and topoisomerase II.Exemplary topology isomerase I inhibitor comprises but is not limited to camptothecine, as Irinotecan and hycamtin.Exemplary topoisomerase II inhibitor comprises but is not limited to amsacrine, etoposide, Etoposide phosphate and teniposide.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) anti-angiogenic agent of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) anti-angiogenic agent of effective dose.In some embodiments, this method is used for the treatment of breast carcinoma, pulmonary carcinoma (as a line advanced NSCLC and a NSCLC), ovarian cancer and the melanoma (comprising metastasis melanin tumor) under metastatic breast cancer, auxiliary situation or the newly auxiliary situation.

Many anti-angiogenic agents are identified and are known in the art, comprise those that Carmeliet and Jain (2000) enumerate.Anti-angiogenic agent can be natural appearance or non-natural occur.At some embodiments, chemotherapeutics is synthetic anti-angiogenic peptides.For example, reported once in the past that the anti-angiogenesis activity of little synthetic short apoptosis peptide comprised two functional domains, the CD13 receptor (amino peptidase N) of a targeting on the tumor blood capillary destroys mitochondrial membrane after another internalization.Nat.Med.1999，5(9)：1032-8。Find second filial generation dimer peptide CNGRC-GG-d (KLAKLAK) 2, be called HKP (Hunter Killer Peptide) and have improved anti-tumor activity.Therefore, in some embodiments, anti-angiogenic peptides is HKP.In some embodiments, anti-angiogenic agent except anti-VEGF antibodies (as

).In some embodiments, anti-angiogenic agent is the micromolecular inhibitor (for example VEGFR1, VEGFR2 and/or VEGFR3) of VEGFR.The micromolecular inhibitor of suitable VEGFR includes but not limited to cut down Ta Lani, AZD2171, handkerchief azoles handkerchief Buddhist nun (GW786034), Sutent, AG013736, Sorafenib, ZD6474, XL647 and XL999.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) proteasome inhibitor of effective dose is as bortezomib (bortezomib) (ten thousand Mactra sulcatria Deshayess).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) proteasome inhibitor of effective dose such as bortezomib (ten thousand Mactra sulcatria Deshayess).

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) therapeutic antibodies of effective dose.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) therapeutic antibodies of effective dose.Suitable therapeutic antibodies include but not limited to anti-VEGF antibodies ( (bevacizumab)), anti--HER2 antibody (as

(Herceptin)),

(Cetuximab), Kan Pasi (Campath) (alemtuzumab), Mai Luota (Myelotarg) (gemtuzumab Ozogamicin Mylotarg CDP 771 (gemtuzumab)), Ze Waling (Zevalin) (ibritumomab tiuextan, Mabthera (Rituxan) (Rituximab) and hectogram sand (Bexxar) (tositumomab).In some embodiments, chemotherapeutics is

(Cetuximab).In some embodiments, chemotherapeutics is at the therapeutic antibodies outside the antibody of VEGF or HER2.In some embodiments, this method is used for the treatment of the positive breast carcinoma of HER2, comprises the treatment advanced breast cancer, treats metastatic carcinoma, treats breast carcinoma and the new cancer of assisting under the situation of treatment under the auxiliary situation.In some embodiments, this method is used for the treatment of following any disease: under metastatic breast cancer, the auxiliary situation or breast carcinoma, pulmonary carcinoma (as a line advanced NSCLC and a NSCLC), ovarian cancer, head and neck cancer and melanoma (comprising metastasis melanin tumor) under the newly auxiliary situation.For example, in some embodiments, provide the method for the positive metastatic breast cancer of HER2 in the treatment individuality, comprised giving individual about 54mg in Nanoparticulate compositions weekly to 540mg rapamycin or about 30mg/m ²To 300mg/m ²Rapamycin continued for 3 weeks, the 4th all drug withdrawals, parallel giving

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) VEGF antibody of effective dose.In some embodiments, the collaborative cell proliferation (for example growth of tumour cell) that suppresses of the rapamycin or derivatives thereof Nanoparticulate compositions of effective dose and VEGF antibody.It is in some embodiments, about at least 10% that (comprise for example at least approximately following arbitrary: cell proliferation 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) is suppressed.In some embodiments, the rapamycin or derivatives thereof is a rapamycin.In some embodiments, VEGF antibody be bevacizumab (for example

).In some embodiments, the rapamycin or derivatives thereof in the nano-particle is given by intravenous administration in the compositions.In some embodiments, VEGF antibody is given by intravenous administration.In some embodiments, rapamycin or derivatives thereof and the VEGF antibody in the Nanoparticulate compositions all is given by intravenous administration.

In some embodiments, the invention provides the method that suppresses cancer metastasis in the individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) VEGF antibody of effective dose.In some embodiments, the collaborative neoplasm metastasis that suppresses of the rapamycin or derivatives thereof Nanoparticulate compositions of effective dose and VEGF antibody.It is in some embodiments, about at least 10% that (comprise for example at least approximately following arbitrary: transfer 20%, 30%, 40%, 60%, 70%, 80%, 90% or 100%) is suppressed.In some embodiments, provide the method that suppresses to transfer to lymph node.In some embodiments, provide the method that suppresses to transfer to lung.In some embodiments, the rapamycin or derivatives thereof is a rapamycin.In some embodiments, VEGF antibody be bevacizumab (for example

).In some embodiments, the rapamycin or derivatives thereof in the nano-particle is used by intravenous and is given in the compositions.In some embodiments, VEGF antibody is used by intravenous and is given.In some embodiments, rapamycin or derivatives thereof in the Nanoparticulate compositions and VEGF antibody are all used by intravenous and are given.

In some embodiments, the rapamycin or derivatives thereof except in Nanoparticulate compositions also gives two or more chemotherapeutics.These two or more chemotherapeutics can (but needn't) belong to inhomogeneous chemotherapeutics.This paper provides the example of these combinations.Also consider other combination.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) antimetabolite of effective dose (as nucleoside analog, for example, gemcitabine); And c) anthracycline antibiotics (as epirubicin).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) antimetabolite of effective dose (as nucleoside analog, for example, gemcitabine); C) anthracycline antibiotics of effective dose (as epirubicin).In some embodiments, this method is used for the treatment of the breast carcinoma under the new auxiliary situation.For example, in some embodiments, provide treatment individual local late period/inflammatory method for cancer, comprised giving individual rapamycin (about 30mg/m for example in Nanoparticulate compositions ²To about 300mg/m ²Or for example about 50mg is to the 540mg rapamycin), per 2 weeks give; 2000mg/m ²Gemcitabine, per 2 weeks give; And 50mg/m ²Epirubicin, per 2 weeks give.In some embodiments, provide the method for breast carcinoma in the individuality under the auxiliary situation of treatment, comprised giving individual rapamycin (for example about 30mg/m in Nanoparticulate compositions ²To about 300mg/m ²Or for example about 50mg is to the 540mg rapamycin), per 2 weeks give 2000mg/m ²Gemcitabine, per 2 weeks give, and 50mg/m ²Epirubicin, per 2 weeks give.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) medicament based on platinum of effective dose (as carboplatin), and c) therapeutic antibodies (as anti--HER2 antibody (as

) and anti-VEGF antibodies (as

)).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) medicament based on platinum of effective dose (as carboplatin), and c) therapeutic antibodies (as anti--HER2 antibody (as

) and anti-VEGF antibodies (as )).In some embodiments, this method is used for the treatment of following any disease: breast carcinoma and pulmonary carcinoma (comprising NSCLC and advanced NSCLC) under advanced breast cancer, metastatic breast cancer, the auxiliary situation.In some embodiments, provide the method for metastatic carcinoma in the treatment individuality, comprised giving individual rapamycin (for example about 30mg/m in Nanoparticulate compositions ²To about 300mg/m ²Or for example about 50mg is to the 540mg rapamycin) and carboplatin, AUC=2, wherein administration weekly gave for 3 weeks, the 4th not administration of week.In some embodiments, this method also comprises weekly the Trastuzumab of about 2-4mg/kg

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) medicament based on platinum of effective dose (as carboplatin), and c) vincaleucoblastine (as

).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) medicament based on platinum of effective dose (as carboplatin), and c) vincaleucoblastine (as

).In some embodiments, this method is used for the treatment of pulmonary carcinoma.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) anthracycline antibiotics (as the adriamycin) alkylating agent of effective dose (as cyclophosphamide), and c).In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) anthracycline antibiotics (as the adriamycin) alkylating agent of effective dose (as cyclophosphamide), and c).In some embodiments, this method is used for the treatment of breast carcinoma of early stage.In some embodiments, this method is used for the treatment of the breast carcinoma under auxiliary situation or the newly auxiliary situation.For example, in some embodiments, provide the method for breast carcinoma of early stage in the treatment individuality, comprised rapamycin (for example about 30mg/m that gives in Nanoparticulate compositions ²To about 300mg/m ²Or for example 50mg to the 540mg rapamycin), 60mg/m ²Adriamycin and 600mg/m ²Cyclophosphamide, wherein per 2 all administrations 1 time.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) the p110 α-specific inhibitor of effective dose (for example PX-866).In some embodiments, this method also comprises the tyrosine kinase inhibitor (for example gefitinib or Te Luokai) that gives effective dose.In some embodiments, cancer is a nonsmall-cell lung cancer.

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) chemical compound that influences the MAPK approach of effective dose (for example Sorafenib (BAY49-9006)).In some embodiments, this method also comprises the tyrosine kinase inhibitor (for example gefitinib or Te Luokai) that gives effective dose.In some embodiments, cancer is a nonsmall-cell lung cancer.In some embodiments, cancer is the brain cancer (a for example glioblastoma).

In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) influence of effective dose participates in the another kind of medicament of the signal transduction path of rapamycin target.In some embodiments, the invention provides method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) influence of effective dose participates in the another kind of medicament of the signal transduction path of mTOR.In some embodiments, other medicament influence participates in the signal transduction path of TORC1.In some embodiments, other medicament influence participates in the signal transduction path of mTORC2.The signal transduction path that participates in mTOR includes but not limited to PI3K/Akt approach and cAMP/AMPK approach.These approach are to be mutually related.Therefore, the medicament that influences a kind of signal transduction path often influences other approach (directly or indirectly).

In some embodiments, the signal transduction path of participation mTOR is the PI3K/Akt signal transduction path.For example, in some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) activatory another medicament of the inhibition PI3K/Akt of effective dose.In some embodiments, cancer is any in HER2+ breast carcinoma, chronic granulocytic leukemia CML, ovarian cancer, carcinoma of endometrium, sarcoma, SCCHN (head and neck squamous cell carcinoma) and the thyroid carcinoma.

PI3/Akt signal transduction path described herein comprises any member or the composition of this signal transduction cascade system of any direct or indirect participation (signal transduction cascade).These include but not limited to PI3 kinases, Akt, PDK1, RAPTOR (if mTOR regulates associated protein), TSC1 (tuberous sclerosis synthesis 1), TSC2, PTEN (phosphate and tensin (tenesin) congener) and downstream effect thing such as cyclin D, HIF1, HIF2, Glut1, LAT1 and c-Myc.The composition of PI3/Akt signal transduction path also can comprise RHEB, Rictor, S6K, 4EBP1, cAMP, cAMPK, G β L, IRS, PIP2, PIP3, Rho, Ras, Abl, PKC, eIF4E, PDGFR, VEGFR and VHL.Therefore, the medicament of influence (as suppress) PI3K/Akt signal transduction path can be by working to any or a plurality of adjustings in these compositions.

In some embodiments, other medicament suppresses PI3 kinases (PI3K).Suitable PI3K inhibitor comprises but is not limited to wortmannin and its derivant or analog; Celecoxib and its analog be OSU-03012 and OSU-03013 for example; 3-deoxidation-D-inositol analog, for example PX-316; 2 '-replacement 3 '-deoxidation-phosphatidyl-inositol analog; Condensed heteroaryl derivatives; 3-(imidazo [1,2-a] pyridin-3-yl) derivant; Ly294002; Quinazoline-4-one derivatives, for example IC486068; The benzothiophene derivative that 3-(mixing) aryloxy group replaces; Viridin, it comprises for example PX-866 (acetic acid (1S, 4E, 10R of semisynthetic viridin, 11R, 13S, 14R)-[4-diallyl aminomethylene-6-hydroxyl-1-methoxyl methyl-10,13-dimethyl-3,7,17-trioxy--1,3,4,7,10,11,12,13,14,15,16,17-ten dihydros-2-oxa--Pentamethylene. [a] phenanthrene-11-base ester); With wortmannin and derivant thereof.

In some embodiments, other medicament suppresses the Akt kinases, and described Akt kinases comprises Akt1, Akt2 and Akt3.In some embodiments, other medicament suppresses the phosphorylation of the kinase whose S473 of people Akt, but does not suppress the phosphorylation of T308.In some embodiments, second kind of chemical compound suppresses the phosphorylation of the kinase whose T308 of people Akt, but is not S473.In some embodiments, other medicament suppresses the phosphorylation of kinase whose S473 of people Akt and T308.In some embodiments, other medicament is intervened the kinase whose film of Akt location.Proper A kt inhibitors of kinases includes but not limited to Akt-1-1 (suppressing Akt1), Akt-1-1,2 (suppressing Akt1 and 2), API-59CJ-Ome, 1-H-imidazo [4,5-c] pyridinyl compounds, Indole-3-carbinol and derivant thereof, perifosine, phosphatidyl-4 alcohol ether lipid are like thing, triciribine (TCN or API-2 or NCI identifier: NSC154020).In some embodiments, other medicament is a perifosine.

In some embodiments, other medicament is the PDK1 inhibitor.

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) the another kind of medicament of the inhibition cyclin D1 of effective dose (for example cyclin D1 overexpression).In some embodiments, cancer is any in lymphoma mantle cell and the breast carcinoma.

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) the another kind of medicament of the inhibition Myc overexpression of effective dose.In some embodiments, cancer is a Burkitt lymphoma.

In some embodiments, other medicament suppresses HIF.In some embodiments, HIF is HIF1.In some embodiments, HIF is HIF2.In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) the another kind of medicament of the inhibition HIF of effective dose (for example HIF overexpression).In some embodiments, other medicament suppresses the blood vessel generation of HIF-mediation.In some embodiments, cancer is RCC and Von Hippel-Lindau disease (VHL).

Other PI3K/Akt signal transduction path inhibitor comprises but is not limited to for example FTY720 and UCN-01.

Though medicament described herein is sometimes referred to as the signal transduction path inhibitor, method described herein comprises uses these inhibitor for treating cancers, and no matter the mechanism of action or how to obtain therapeutic effect.Really, will be appreciated that: when giving the subject, or obtain its treatment effectiveness whereby, these chemical compounds may have more than a target, and the initial activity that chemical compound is generally acknowledged may not be its activity that has in vivo.Therefore, to chemical compound as by way of or the description of albumen target (for example Akt or mTOR) inhibitor show that chemical compound has this activity, when being used as therapeutic agent or preventive, have this kind activity but never limit chemical compound.

Can comprise for example inhibitor of husband's degree of evening up, antifolate, SN38, breast carcinoma resistance protein (for example KO143 and FT C) with other medicament that rapamycin described herein (or derivatives thereof) compositions is united use.

In some embodiments, provide the method for the individual middle and advanced stage breast carcinoma of treatment, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) carboplatin of effective dose.In some embodiments, this method also comprises and to give individual effective dose

In some embodiments, provide the method for metastatic breast cancer in the treatment individuality, comprised giving individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle, b) gemcitabine of effective dose.In some embodiments, provide the method for the treatment of individual middle and advanced stage nonsmall-cell lung cancer, comprised giving individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle, b) carboplatin of effective dose.

In some embodiments, this method also comprises: according to the hormone receptor situation of the patient with the tumor tissues of not expressing ER and PgR identification cancer patient crowd's (for example breast carcinoma), and give to contain comprising of this patient crowd's effective dose the compositions of the nano-particle of rapamycin or derivatives thereof and carrier protein (for example albumin).In some embodiments, this method also comprises at least a other chemotherapeutics that gives patient crowd's effective dose.At least a other chemotherapeutics can or one after the other give with the rapamycin or derivatives thereof nano-particle while.In some embodiments, at least a other chemotherapeutics comprises simultaneously or 5-fluorouracil, epirubicin and the cyclophosphamide (FEC) that give in succession.These methods can have higher effectiveness in ER (-)/PgR (-) crowd among all HER-2 positives and the HER-2 negative patients crowd.

In some embodiments of in above and chemotherapeutics combinational therapeutic methods any, provide to comprise and contained rapamycin or derivatives thereof and the nano-particle of carrier protein (for example albumin) and the compositions of at least a other chemotherapeutics.Compositions described herein can comprise the rapamycin or derivatives thereof of effective dose and the chemotherapeutics of treatment cancer.In some embodiments, there are weight ratio for example described herein in chemotherapeutics and rapamycin or derivatives thereof with predetermined ratio in compositions.In some embodiments, the invention provides the cooperative compositions of at least a other chemotherapeutics of the compositions of the nano-particle that contains the rapamycin or derivatives thereof comprising of effective dose and effective dose.

In some embodiments of in above and chemotherapeutics combinational therapeutic methods any, the invention provides the pharmaceutical composition that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), it is applied to treat cancer, and wherein said application comprises the while and/or gives at least a other chemotherapeutics in succession.In some embodiments, the invention provides the pharmaceutical composition that comprises chemotherapeutics, it is applied to treat cancer, and wherein said application comprises simultaneously and/or comprise in succession the compositions of the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin).In some embodiments, the invention provides the Nanoparticulate compositions that contains the rapamycin or derivatives thereof and the compositions that comprises a kind of other chemotherapeutics, with simultaneously and/or be used for the treatment of cancer in succession.

In some embodiments, the invention provides the treatment method for cancer, it comprises the compositions of the nano-particle that gives to contain comprising of individual effective dose rapamycin or derivatives thereof and carrier protein (for example albumin), with operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment and/or photodynamic therapy simultaneously and/or carry out in succession.In some embodiments, the invention provides the treatment method for cancer, it comprises: first therapy comprises comprising rapamycin and albuminous nano-particle; With second therapy, it comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment and/or photodynamic therapy.In some embodiments, cancer can be a carcinoma of prostate.In some embodiments, second therapy is a hormonotherapy.In some embodiments, second therapy is a radiotherapy.In some embodiments, second therapy is operation.

Giving rapamycin or derivatives thereof Nanoparticulate compositions can be before hormonotherapy, radiation and/or operation, after hormonotherapy, radiation and/or operation, or parallel with hormonotherapy, radiation and/or operation.For example, giving rapamycin or derivatives thereof Nanoparticulate compositions can be before or after hormonotherapy, radiation and/or operative therapy, blanking time scope from several minutes to several weeks.In some embodiments, the time period between first therapy and second therapy makes rapamycin or derivatives thereof and carrier protein (for example albumin) and hormonotherapy, radiation and/or operation still can apply favourable combined effect by pair cell.In some embodiments, the extended treatment time period can be desirable significantly, wherein between two kinds of therapies at interval a couple of days to several weeks.

Operation described herein comprises that the cancerous tissue of all or part is by physical removal, excision and/or destructive excision.Tumorectomy refers to physical removal to the small part tumor.Except tumorectomy, comprise laser surgery, cryosurgery, electrosurgical and micro-control operation (micropically controlled surgery (mohs' technique, (Mohssurgery)) by the treatment of performing the operation.Also consider removing of shallow-layer operation, preceding cancer or normal structure.

Except giving chemotherapeutics, can carry out hormonotherapy, radiotherapy and/or operation.For example, individuality can at first contain Nanoparticulate compositions and at least a other chemotherapeutics of rapamycin or derivatives thereof and stand hormonotherapy, radiotherapy and/or operation subsequently.Alternatively, individuality at first can be used hormonotherapy, radiotherapy and/or operative treatment, gives Nanoparticulate compositions and at least a other chemotherapeutics then.Also can consider other combination.

More than disclosed and the chemotherapeutics Nanoparticulate compositions of uniting give same being suitable for and those of hormonotherapy, radiotherapy and/or operation associating.

Lose the hormone blocking-up of therapy, hormone ablation, associating, intermittently hormonotherapy, auxiliary hormonotherapy, auxiliary androgen inhibition newly and newly auxiliary androgen forfeiture newly as include but not limited to androgen ablation, androgen in term hormonotherapy used herein.Androgen for example testosterone is regulated growth, differentiation and apoptosis rate in prostate and its malignant diseases.In some embodiments, carcinoma of prostate can utilize carcinoma of prostate that androgenic extensive dependency is treated by several therapies that are called hormonotherapy.

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) promoting sexual gland hormone-releasing hormone of effective dose (GnRH) agonist (being also referred to as the LHRH agonist, the LHRH agonist).In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) the GnRH agonist of effective dose.In some embodiments, this method is used for the treatment of carcinoma of prostate.In some embodiments, the invention provides the pharmaceutical composition that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), it is applied to treat cancer, and wherein said application comprises the while and/or gives at least a GnRH agonist in succession.Suitable treatment GnRH agonist includes but not limited to leuprorelin, goserelin, nafarelin, meterelin, buserelin, histrelin, deslorelin and triptorelin.

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; B) the GnRH agonist of effective dose; And c) androgen antagonist.In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; B) the GnRH agonist of effective dose; And c) androgen antagonist.In some embodiments, this method is used for the treatment of carcinoma of prostate.In some embodiments, give androgen antagonist with the GnRH agonist and/or beginning before containing the Nanoparticulate compositions treatment of rapamycin.In some embodiments, the invention provides the pharmaceutical composition that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), it is used for the treatment of cancer, and wherein said application comprises the while and/or gives at least a GnRH agonist or androgen antagonist in succession.In some embodiments, giving androgen antagonist is at the GnRH agonist and/or before containing the Nanoparticulate compositions of rapamycin, and gives the androgen antagonist continuity GnRH agonist therapy of first month at least.In some embodiments, give androgen antagonist with the GnRH agonist and/or contain that any in about 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23 and 24 weeks begins before the Nanoparticulate compositions treatment of rapamycin.Suitable treatment GnRH agonist includes but not limited to leuprorelin, goserelin, nafarelin, meterelin, buserelin, histrelin, deslorelin and triptorelin.Suitable treatment androgen antagonist include but not limited to bicalutamide (Casodex), flutamide (flutamide), cyproterone, nilutamide (Ni Luta amine) and other in the final circulation androgen level that reduces to the effective therapeutic agent of castrating level.

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) promoting sexual gland hormone-releasing hormone of effective dose (GnRH) antagonist (being also referred to as lhrh antagonist, the LHRH antagonist).In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) the GnRH antagonist of effective dose.In some embodiments, this method is used for the treatment of carcinoma of prostate.In some embodiments, this method provides the pharmaceutical composition that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin), it is applied to treat cancer, and wherein said application comprises the while and/or gives at least a GnRH antagonist in succession.Suitable treatment GnRH antagonist includes but not limited to ganirelix acetate (Antagon), 1: PN: WO02056903 PAGE: 25 claimed protein (Plenaxis) of cetrorelix acetate (Cetrotide), the Organon International of Serono etc.

In embodiment, what this method was included in that following any or a plurality of time treats effective dose contains the rapamycin Nanoparticulate compositions with the treatment carcinoma of prostate: before the hormonotherapy, with hormonotherapy, during hormonotherapy or after the hormonotherapy.In some embodiments, this method comprise with the hormone therapy agent simultaneously or separate treat effective dose contain the rapamycin Nanoparticulate compositions with the treatment carcinoma of prostate.Uniting in tumor of prostate of one or more standard hormone therapy medicines of treatment effective dose and the rapamycin or derivatives thereof of the treatment effective dose in Nanoparticulate compositions suppresses can cause synergism in (comprising disappearing of existing tumor of prostate).

In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) of effective dose; And b) Endothelin of effective dose-A receptor antagonist, inhibitor or antagonist.In some embodiments, provide method for cancer in the treatment individuality, it comprises and gives individuality: a) effective dose comprises the compositions that contains rapamycin and albuminous nano-particle; And b) Endothelin of effective dose-A receptor antagonist, inhibitor or antagonist.In some embodiments, this method is used for the treatment of carcinoma of prostate (for example advanced prostate cancer).In some embodiments, the invention provides and comprise the pharmaceutical composition that contains rapamycin or derivatives thereof and carrier protein (for example albumin), it is applied to treat cancer, and wherein said application comprises the while and/or gives at least a Endothelin-A receptor antagonist, inhibitor or antagonist in succession.Suitable treatment Endothelin-A receptor antagonist, inhibitor or antagonist include but not limited to atrasentan (ABT627, Abbott Laboratories, Abbott Park, IL).

It should be understood that any method of treatment cancer described herein (part of for example above " treatment cancer method ") is suitable for and comprises the description of conjoint therapy.In any some embodiments of the Therapeutic Method relevant with conjoint therapy described herein, with give any therapy separately and compare, uniting the treatment of carrying out and to produce and add up or even the result of collaborative (for example, greater than add up) with first therapy (Nanoparticulate compositions that for example comprises rapamycin or derivatives thereof and carrier protein) and second therapy (for example to one or more useful chemical compounds of treatment cancer).In some embodiments, compare with the normally used amount of independent therapy, every kind of pharmaceutically active compound of low amount is used as the part of conjoint therapy.Preferably, use conjoint therapy and compare, obtain identical or bigger treatment benefit by in the individualized compound of independent use any.In some embodiments, compare, in conjoint therapy, use more in a small amount the pharmaceutically active compound of (for example than low dosage or less frequency dosage regimen) to obtain identical or bigger treatment benefit with normally used amount in the independent therapy.Preferably, use pharmaceutically active compound in a small amount to cause the minimizing of quantity, seriousness, frequency or the persistent period of one or more side effect relevant with chemical compound.

In any some embodiments of the Therapeutic Method relevant with conjoint therapy, (for example chemotherapeutics and/or hormone therapy agent) exists at least in containing the single compositions of two kinds of different nano-particle the rapamycin or derivatives thereof with second kind of chemical compound, wherein the nano-particle of some in compositions comprises rapamycin or derivatives thereof and carrier protein, and some other nano-particle in compositions comprise second kind of pharmaceutically active compound and carrier protein.In some embodiments, have only the rapamycin or derivatives thereof to be included in the nano-particle.In some embodiments, rapamycin or derivatives thereof and the second kind of chemical compound that gives simultaneously in Nanoparticulate compositions can combine with the additional dosage of rapamycin and/or second kind of chemical compound.

In about any some embodiments of the above-mentioned embodiment of conjoint therapy described herein, give first and second therapies in same compositions or in the compositions of separating simultaneously.In some embodiments, give first and second therapies in succession, that is, first therapy gave before or after first and two therapies give.In some embodiments, the giving of first and second therapies carried out simultaneously, that is, overlap each other during the giving of first therapy and during the giving of second therapy.In some embodiments, first and second therapies give do not carry out simultaneously.For example, in some embodiments, give first therapy and stop before second therapy giving.In some embodiments, giving second therapy stops before first therapy giving.In some embodiments, second therapy is a radiotherapy.In some embodiments, second therapy is operation.

In about any some embodiments of the above-mentioned embodiment of conjoint therapy, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurrence cancer, auxiliary situation cancer, newly auxiliary situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say except carcinoma).In some embodiments, cancer is not colon cancer (that is to say except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.

In about any some embodiments of the above-mentioned embodiment of conjoint therapy, do not give individual taxane.In some embodiments, the taxane that gives is not a Nanoparticulate compositions.In some embodiments, the Nanoparticulate compositions that comprises the rapamycin or derivatives thereof does not give with taxane.In some embodiments, individuality accepting one or Nanoparticulate compositions time period that comprises the rapamycin or derivatives thereof of multiple dose during, do not give individual taxane.In some embodiments, before beginning, individual with the taxane treatment with the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof.For example, begin with before the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individuality can accept one or many days, week, month or year taxane.In other embodiments, begin with before the Nanoparticulate compositions treatment that comprises the rapamycin or derivatives thereof, individuality is never accepted taxane.In some embodiments, after the Nanoparticulate compositions treatment termination that comprises the rapamycin or derivatives thereof, individual body and function taxane treatment.In other embodiments, after the Nanoparticulate compositions treatment termination that comprises the rapamycin or derivatives thereof, individual from treating without taxane.In some embodiments, compositions, first therapy and/or second therapy do not comprise taxane.In other embodiments, compositions, first therapy and/or second therapy comprise taxane.Dosage and medication

The dosage that gives the present composition of individuality (for example people) can and changed by the concrete stage of treatment cancer along with concrete compositions, medication.This dosage should be enough to produce required reaction, as treatment for cancer or prevention are replied.In some embodiments, the amount of said composition is the treatment effective dose.In some embodiments, the amount of said composition is the prevention effective dose.In some embodiments, when giving compositions to individuality, the amount of rapamycin or derivatives thereof is to induce toxicological effect (toxicological effect) (promptly in compositions, in the effect more than the clinical acceptable toxic level) below level, or the level that can control or stand in potential side effect.

In some embodiments, the amount of rapamycin or derivatives thereof is such amount in compositions, it is enough to increase substrate AKT (basal AKT) activity, increase the AKT phosphorylation, increase the PI3-kinase activity, increase the activatory length of AKT (for example, by the inductive activation of the IGF-1 of external source), the serine phosphorylation that suppresses IRS-1, suppress the IRS-1 degraded, suppress or change CXCR4 Subcellular Localization, suppress the VEGF secretion, reduce the expression of cyclin D2, reduce the expression of survivin, suppress the inductive multiple myeloma cells growth of IL-6-, anticancer propagation, increase apoptosis, increase cell cycle arrest, increase the cracking of poly-(ADP ribose) polymerase, increase the cracking of caspase-8/ caspase-9, change or be suppressed at phosphatidyl-inositol 3-kinase/AKT/mTOR and/or cyclin D1/retinoblastoma by way of in the signal conduction, suppressing blood vessel takes place and/or suppresses osteoclast to form.

In some embodiments, the invention provides method for cancer in the combination treatment individuality of the nano-particle by giving to contain comprising of individuality (for example people) effective dose rapamycin or derivatives thereof and carrier protein (for example, albumin such as human serum albumin).In some embodiments, the amount of rapamycin or derivatives thereof is included in arbitrary following ranges in compositions: about 0.5 to about 5mg, about 5 to about 10mg, about 10 to about 15mg, about 15 to about 20mg, about 20 to about 25mg, about 20 to about 50mg, about 25 to about 50mg, about 50 to about 75mg, about 50 to about 100mg, about 75 to about 100mg, about 100 to about 125mg, about 125 to about 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 to about 300mg, about 300 to about 350mg, about 350 to about 400mg, about 400 to about 450mg or about 450 to about 500mg.In some embodiments, in the compositions of effective dose the amount of (for example unit dosage forms) rapamycin or derivatives thereof be from about 54mg to about 540mg scope, for example approximately 180mg to the scope of about 270mg, or about 216mg.In some embodiments, the concentration of rapamycin is (approximately 0.1mg/ml) or spissated (approximately 100mg/ml) of dilution in compositions, comprises for example following any: about 0.1 to about 50mg/ml, about 0.1 to about 20mg/ml, about 1 to about 10mg/ml, approximately 2mg/ml is to about 8mg/ml, about 4 to about 6mg/ml, about 5mg/ml.In some embodiments, the concentration of rapamycin is at least approximately following any: 0.5mg/ml, 1.3mg/ml, 1.5mg/ml, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 40mg/ml or 50mg/ml.

The exemplary effective dose of the rapamycin or derivatives thereof in Nanoparticulate compositions includes but not limited to approximately following any rapamycin: 25mg/m ², 30mg/m ², 50mg/m ², 60mg/m ², 75mg/m ², 80mg/m ², 90mg/m ², 100mg/m ², 120mg/m ², 160mg/m ², 175mg/m ², 180mg/m ², 200mg/m ², 210mg/m ², 220mg/m ², 250mg/m ², 260mg/m ², 300mg/m ², 350mg/m ², 400mg/m ², 500mg/m ², 540mg/m ², 750mg/m ², 1000mg/m ²Or 1080mg/m ²In various embodiments, compositions comprises approximately following any following rapamycin or derivatives thereof: 350mg/m ², 300mg/m ², 250mg/m ², 200mg/m ², 150mg/m ², 120mg/m ², 100mg/m ², 90mg/m ², 50mg/m ²Or 30mg/m ²The amount of the rapamycin or derivatives thereof that at every turn gives in some embodiments, is approximately following below any: 25mg/m ², 22mg/m ², 20mg/m ², 18mg/m ², 15mg/m ², 14mg/m ², 13mg/m ², 12mg/m ², 11mg/m ², 10mg/m ², 9mg/m ², 8mg/m ², 7mg/m ², 6mg/m ², 5mg/m ², 4mg/m ², 3mg/m ², 2mg/m ²Or 1mg/m ²In some embodiments, the effective dose of rapamycin or derivatives thereof is to be included in arbitrary following ranges in compositions: about 1 to about 5mg/m ², about 5 to about 10mg/m ², about 10 to about 25mg/m ², about 25 to about 50mg/m ², about 50 to about 75mg/m ², about 75 to about 100mg/m ², about 100 to about 125mg/m ², about 125 to about 150mg/m ², about 150 to about 175mg/m ², about 175 to about 200mg/m ², about 200 to about 225mg/m ², about 225 to about 250mg/m ², about 250 to about 300mg/m ², about 300 to about 350mg/m ², or about 350 to about 400mg/m ²Preferably, the effective dose of rapamycin or derivatives thereof is about 30 to about 300mg/m in the compositions ², for example about 100 to about 150mg/m ², about 120mg/m ², about 130mg/m ²Or about 140mg/m ²

In aspect above in some embodiments of any, in the compositions effective dose of rapamycin or derivatives thereof comprise at least approximately following any: 1mg/kg, 2.5mg/kg, 5mg/kg, 7.5mg/kg, 10mg/kg, 15mg/kg or 20mg/kg.In various embodiments, the rapamycin or derivatives thereof of effective dose comprises approximately following any following rapamycin or derivatives thereof in the compositions: 350mg/kg, 300mg/kg, 250mg/kg, 200mg/kg, 150mg/kg, 100mg/kg, 50mg/kg, 25mg/kg, 20mg/kg, 10mg/kg, 5mg/kg or 1mg/kg.

Exemplary administration frequency (dosing frequency) includes but not limited to: weekly, and not at interval; In 4 weeks, gave for 3 weeks weekly; Per 3 weeks 1 time: per 2 weeks 1 time; In 3 weeks, gave for 2 weeks weekly.In some embodiments, approximately per 2 weeks 1 time, per 3 weeks 1 time, per 4 weeks 1 time, per 6 weeks 1 time or per 8 weeks give compositions 1 time.In some embodiments, give in a week compositions about at least 1 time, 2 times, 3 times, 4 times, 5 times, 6 times or in 7 times (that is every day) any.In some embodiments, the interval between at every turn giving in approximately June, March, January, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day arbitrary below.In some embodiments, more than arbitrary in approximately January, February, March, April, May, June, August or 12 months of the interval between at every turn giving.In some embodiments, in dosage regimen, do not have at interval.In some embodiments, no more than about 1 week of interval between each administration.

The time period that the giving of compositions can continue to prolong, for example from about January up to about 7 years.In some embodiments, compositions at least approximately following arbitrary during in give: 2,3,4,5,6,7,8,9,10,11,12,18,24,30,36,48,60,72 or 84 months.In some embodiments, during at least 1 month, give the rapamycin or derivatives thereof, the no more than about week of interval between wherein each administration, and wherein when each administration the dosage of rapamycin or derivatives thereof be about 0.25mg/m ²To about 75mg/m ², for example about 0.25mg/m ²To about 25mg/m ²Or about 25mg/m ²To about 50mg/m ²

In some embodiments, when giving based on 3 all schemes, the dosage range of rapamycin can be 100-400mg/m in the Nanoparticulate compositions ², maybe when giving when scheme gives weekly, the dosage range of rapamycin can be 50-250mg/m in the Nanoparticulate compositions ²Preferably, the amount of rapamycin is about 80 to about 180mg/m ²(for example about 100mg/m ²To about 150mg/m ², as about 120mg/m ²).

Other exemplary dosage regimen that Nanoparticulate compositions (thunderous handkerchief mycin/albuminous Nanoparticulate compositions) gives includes but not limited to: 100mg/m ², weekly, be not interrupted; 75mg/m ², weekly, in 4 weeks, gave for 3 weeks; 100mg/m ², weekly, in 4 weeks, gave for 3 weeks; 125mg/m ², weekly, in 4 weeks, gave for 3 weeks; 125mg/m ², weekly, in 3 weeks, gave for 2 weeks; 130mg/m ², weekly, be not interrupted; 175mg/m ², per 2 weeks 1 time; 260mg/m ², per 2 weeks 1 time; 260mg/m ², per 3 weeks 1 time; 180-300mg/m ², per 3 weeks; 60-175mg/m ², weekly, be not interrupted; 20-150mg/m ², a week 2 times; And 150-250mg/m ², a week 2 times.The administration frequency of compositions can be adjusted according to administration doctor's judgement during treating.

In some embodiments, give compositions about 20 to about 40mg/kg, 1 week 3 times.In some embodiments, the compositions that gives is about 60 to about 120mg/m ², 1 the week 3 times, or every day about 90mg/m ²In some embodiments, give the compositions of about 30mg/kg every day.In some embodiments, provide the method for the treatment of multiple myelomas according to these dosage regimens.

Aspect another, the invention provides the compositions that gives effective dose by parenteral and treat method for cancer in the individuality to individual (for example people), described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin, as the human serum albumin).In some embodiments, medicine-feeding way is intravenous, intra-arterial, intramuscular or subcutaneous.In various embodiments, each dosage gives about 54mg arrives about 270mg or about 216mg to about 540mg such as about 180mg rapamycin or derivatives thereof.In some embodiments, taxane is not included in the compositions.In some embodiments, the rapamycin or derivatives thereof be in compositions, contain be used for the treatment of cancer forms of pharmacologically active agents only arranged.

Compositions described herein can give individuality (as the people) by number of ways, comprises in, ophthalmic interior, subcutaneous as (intravesicular), intramuscular in intravenous, intra-arterial, intraperitoneal, the lung, in the per os, suction, capsule, trachea, the sheath, strides mucosa or percutaneous.In some embodiments, can use lasting, the continuous release formulations of compositions.For example, can give the present composition with the treatment respiratory passage diseases by sucking.Can breathe for example pulmonary fibrosis of disease, bronchiolitis obliterans, pulmonary carcinoma, bronchovesicular cancer etc. with combination treatment.In one embodiment of the invention, the nano-particle of The compounds of this invention (for example albumin nanometer granule) can give by any approach of accepting, and includes but not limited to per os, intramuscular, percutaneous, intravenous, passes through the delivery system of inhaler or other air-borne transmission etc.In some embodiments, the rapamycin or derivatives thereof does not have coating (bag quilt) support or is not to use support to give.

Containing the Nanoparticulate compositions of rapamycin and administration frequency judgement according to the administration doctor during treating of second kind of chemical compound can adjust.In some embodiments, first and second therapies simultaneously, give in succession or concurrently.When separately giving, Nanoparticulate compositions and second kind of chemical compound of containing rapamycin can give with different dosing frequency or interval.For example, the Nanoparticulate compositions that contains rapamycin can give weekly 1 time, and second kind of chemical compound can give with either large or small frequency.In some embodiments, can use the continuing of the nano-particle that contains rapamycin and/or second kind of chemical compound, continuous release formulations.The various preparations and the device that obtain to continue to discharge are known in this area.Can use the combination of administration configuration described herein (administration configuration).The mode of conjoint therapy administration

In some embodiments, the invention provides the treatment method for cancer, it comprises: first therapy, and it comprises the nano-particle that comprises rapamycin or derivatives thereof and carrier protein (for example albumin); With second therapy, it comprises chemotherapy and/or hormonotherapy.In some embodiments, this method comprises: a) first therapy, and it comprises and gives the compositions that individuality comprises rapamycin and albuminous nano-particle; And b) second therapy, it comprises chemotherapy and/or hormonotherapy.

In conjoint therapy, the dosage that gives the present composition of individuality (for example people) can and changed by the moment of treatment cancer along with concrete compositions, medication.This amount should enough produce the response of wanting, for example to treatment for cancer or prevention response.In some embodiments, the amount of compositions is the treatment effective dose.In some embodiments, the amount of compositions is the prevention effective dose.In some embodiments, when compositions is given individuality be, the amount of rapamycin or derivatives thereof is in the level of inducing below the toxicological effect (that is, in the effect more than the clinical acceptable toxic level) in compositions, or the level that can control or stand in possible side effect.

(for example administration simultaneously) and/or order (for example order administration) give simultaneously to comprise the compositions (being also referred to as " Nanoparticulate compositions ") of the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin) and chemotherapeutics and/or hormone therapy agent.

In some embodiments, give Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent (comprising specific chemotherapeutics described herein) simultaneously.Term " simultaneously administration " means with no more than about 15 minutes interval to give Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent as used herein, as any time in no more than about 10,5 or 1 minutes at interval.When medicine administration simultaneously, rapamycin or derivatives thereof in the nano-particle and chemotherapeutics and/or hormone therapy agent (for example can be included in the same compositions, the compositions that contains nano-particle and chemotherapeutics) or (for example be included in separately the compositions, nano-particle is included in the compositions, and chemotherapeutics is included in another compositions).For example, the rapamycin or derivatives thereof may reside in the single compositions that contains two kinds of different nano-particle with carrier protein (for example albumin) and chemotherapeutics at least, wherein some nano-particle in the compositions comprise rapamycin or derivatives thereof and carrier protein, and some other nano-particle in the compositions comprise chemotherapeutics and carrier protein.The present invention considers and comprises such compositions.In some embodiments, only contain the rapamycin or derivatives thereof in the nano-particle.In some embodiments, administration can combine with the rapamycin or derivatives thereof of additional dosage and/or chemotherapeutics and/or hormone therapy agent rapamycin or derivatives thereof in the Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent the time.

In some embodiments, rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent give in succession.Term used herein " administration in succession " refers to give rapamycin or derivatives thereof in the Nanoparticulate compositions and chemotherapeutics/or hormone therapy agent with about interval more than 15 minutes, according to appointment above any in 20,30,40,50,60 minutes or more minutes.Can at first give rapamycin or derivatives thereof Nanoparticulate compositions or at first give chemotherapeutics/or hormone therapy agent.Rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent are included in the compositions separately, and they can be included in same packing or the Different Package.

In some embodiments, the walking abreast of rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent promptly, overlaps each other during the giving of Nanoparticulate compositions and during the giving of chemotherapeutics and/or hormone therapy agent.In some embodiments, rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent gives not to be to walk abreast.For example, in some embodiments, before giving chemotherapeutics and/or hormone therapy agent, stop giving rapamycin or derivatives thereof Nanoparticulate compositions.In some embodiments, before giving rapamycin or derivatives thereof Nanoparticulate compositions, stop giving chemotherapeutics and/or hormone therapy agent.Time period between these two non-parallel administrations can be in the scope in about 2 thoughtful 8 weeks, for example about 4 weeks.

According to administration doctor's judgement, can during treating, adjust the administration frequency that contains rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent.When separate administration, can contain rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent with different administration frequencies or interval.For example, can contain rapamycin or derivatives thereof Nanoparticulate compositions weekly, and the administration frequency of chemotherapeutics and/or hormone therapy agent can be higher or lower.In some embodiments, can use lasting, the continuous release formulations that contains rapamycin or derivatives thereof nano-particle and/or chemotherapeutics and/or hormone therapy agent.Realize that the various preparations and the device that continue to discharge are known in this area.

Identical route of administration or different route of administration be can use and rapamycin or derivatives thereof Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent given.(for the while administration with in succession for the administration) in some embodiments, rapamycin or derivatives thereof in the Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent give with predetermined ratio.For example, in some embodiments, the rapamycin or derivatives thereof in Nanoparticulate compositions is about 1 to 1 with the weight ratio of chemotherapeutics or hormone therapy agent.In some embodiments, weight ratio can be about 0.001 than about 1 and about 1000 than between about 1, or about 0.01 than about 1 and 100 than between about 1.In some embodiments, the weight ratio of rapamycin or derivatives thereof in Nanoparticulate compositions and chemotherapeutics or hormone therapy agent be about 100: 1,50: 1,30: 1,10: 1,9: 1,8: 1,7: 1,6: 1,5: 1,4: 1,3: 1,2: 1 and 1: 1 arbitrary below.In some embodiments, the weight ratio of rapamycin or derivatives thereof in Nanoparticulate compositions and chemotherapeutics or hormone therapy agent be about 1: 1,2: 1,3: 1,4: 1,5: 1,6: 1,7: 1,8: 1,9: 1,30: 1,50: 1,100: 1 arbitrary more than.Also consider other ratio.

The required dosage of rapamycin or derivatives thereof and/or chemotherapeutics and/or hormone therapy agent can (but needn't) be lower than the dosage that needs usually when giving each medicament separately.Therefore, in some embodiments, rapamycin or derivatives thereof in the Nanoparticulate compositions of inferior therapeutic dose and/or chemotherapeutics and/or hormone therapy agent are given." inferior therapeutic dose (being lower than the amount of treatment; Subtherapeutic amount) " or " inferior treatment level (be lower than the level of treatment; subtherapeuticlevel) " is meant the amount less than therapeutic dose, that is the amount used usually when giving rapamycin or derivatives thereof in the Nanoparticulate compositions and/or chemotherapeutics and/or hormone therapy agent separately of described amount.This reduction can reflect by the amount that gives in specifying administration and/or the amount that at the appointed time gives in the section reflects (frequency of reduction).

In some embodiments, give enough chemotherapeutics and/or hormone therapy agent, so as to make the normal dose of realizing rapamycin or derivatives thereof in the required Nanoparticulate compositions of identical treatment degree reduce at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or more in arbitrary.In some embodiments, give the or derivatives thereof of the rapamycin in enough Nanoparticulate compositions, so as to make the normal dose of realizing chemotherapeutics that the identical treatment degree is required and/or hormone therapy agent reduce at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or more in arbitrary.

In some embodiments, the dosage of the rapamycin or derivatives thereof in the Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent corresponding normal dose of each medicine when individually dosed is compared all and is reduced.In some embodiments, rapamycin or derivatives thereof in the Nanoparticulate compositions and chemotherapeutics and/or hormone therapy agent are all with inferior treatment level, and promptly the level of Jiang Diing is given.In some embodiments, the dosage of Nanoparticulate compositions and/or chemotherapeutics is significantly less than definite maximum toxicity dose (MTD).For example, the dosage of rapamycin or derivatives thereof Nanoparticulate compositions and/or chemotherapeutics and/or hormone therapy agent is lower than about 50%, 40%, 30%, 20% or 10% of MTD.

Can use the combination of administration configuration as herein described.Combinational therapeutic methods as herein described can carry out separately, perhaps combines with another therapy such as operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormonotherapy, targeted therapy, cryotherapy, ultrasound treatment, photodynamic therapy and/or chemotherapy etc. and carries out.In addition, the people with greater risk of development proliferative disease can receive treatment, to suppress or and/or delay disease progression.

As one of ordinary skill in the understanding, the suitable dose of chemotherapeutics and/or hormone therapy agent is approximately those dosage of having used in clinical treatment, wherein chemotherapeutics and/or hormone therapy agent by independent administration or with other chemotherapeutics administering drug combinations.According to the disease of being treated, possible propellant quantitative changeization.As mentioned above, in some embodiments, can give chemotherapeutics and/or hormone therapy agent with the reduction level.

The dosage of rapamycin or derivatives thereof will change along with the character of conjoint therapy and the disease specific of being treated in the Nanoparticulate compositions.In some embodiments, the amount of the rapamycin or derivatives thereof in the Nanoparticulate compositions is included in any following ranges in therapeutic alliance: about 0.5 to about 5mg, about 5 to about 10mg, about 10 to about 15mg, about 15 to about 20mg, about 20 to about 25mg, about 20 to about 50mg, about 25 to about 50mg, about 50 to about 75mg, about 50 to about 100mg, about 75 to about 100mg, about 100 to about 125mg, about 125 to about 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 to about 300mg, about 300 to about 350mg, about 350 to about 400mg, about 400 to about 450mg or about 450 to about 500mg.In some embodiments, the rapamycin or derivatives thereof amount that is used for the Nanoparticulate compositions (for example unit dosage forms) of the effective dose of conjoint therapy is from about 54mg to about 540mg scope, and for example approximately 180mg arrives about 270mg or about 216mg.In some embodiments, the concentration that is used for the rapamycin in the Nanoparticulate compositions that conjoint therapy uses is dilution (approximately 0.1mg/ml) or spissated (approximately 100mg/ml), comprise for example following any: about 0.1 to about 50mg/ml, about 0.1 to about 20mg/ml, about 1 to about 10mg/ml, approximately 2mg/ml is to about 8mg/ml, about 4 to about 6mg/ml, about 5mg/ml.In some embodiments, the concentration of the rapamycin or derivatives thereof in the Nanoparticulate compositions is at least about any of 0.5mg/ml, 1.3mg/ml, 1.5mg/ml, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 40mg/ml or 50mg/ml in conjoint therapy.

The exemplary effective dose of the rapamycin or derivatives thereof in the Nanoparticulate compositions of using in the conjoint therapy includes but not limited to about 25mg/m ², 30mg/m ², 50mg/m ², 60mg/m ², 75mg/m ², 80mg/m ², 90mg/m ², 100mg/m ², 120mg/m ², 160mg/m ², 175mg/m ², 180mg/m ², 200mg/m ², 210mg/m ², 220mg/m ², 250mg/m ², 260mg/m ², 300mg/m ², 350mg/m ², 400mg/m ², 500mg/m ², 540mg/m ², 750mg/m ², 1000mg/m ²Or 1080mg/m ²In the rapamycin any.In various embodiments, the rapamycin or derivatives thereof in the Nanoparticulate compositions comprises about 350mg/m ², 300mg/m ², 250mg/m ², 200mg/m ², 150mg/m ², 120mg/m ², 100mg/m ², 90mg/m ², 50mg/m ²Or 30mg/m ²In the following rapamycin or derivatives thereof any.The amount of the rapamycin or derivatives thereof that at every turn gives in conjoint therapy in some embodiments, is about 25mg/m ², 22mg/m ², 20mg/m ², 18mg/m ², 15mg/m ², 14mg/m ², 13mg/m ², 12mg/m ², 11mg/m ², 10mg/m ², 9mg/m ², 8mg/m ², 7mg/m ², 6mg/m ², 5mg/m ², 4mg/m ², 3mg/m ², 2mg/m ²Or 1mg/m ²Following any.In some embodiments, the effective dose of rapamycin or derivatives thereof is included in arbitrary following ranges in the compositions of using in conjoint therapy: about 1 to about 5mg/m ², about 5 to about 10mg/m ², about 10 to about 25mg/m ², about 25 to about 50mg/m ², about 50 to about 75mg/m ², about 75 to about 100mg/m ², about 100 to about 125mg/m ², about 125 to about 150mg/m ², about 150 to about 175mg/m ², about 175 to about 200mg/m ², about 200 to about 225mg/m ², about 225 to about 250mg/m ², about 250 to about 300mg/m ², about 300 to about 350mg/m ²Or about 350 to about 400mg/m ²Preferably, the effective dose of rapamycin or derivatives thereof that is used for the compositions of conjoint therapy is about 30 to about 300mg/m ², for example about 100 to about 150mg/m ², about 120mg/m ², about 130mg/m ²Or about 140mg/m ²

In some embodiments of aspect above any, the effective dose of the rapamycin or derivatives thereof in the Nanoparticulate compositions of using in conjoint therapy comprises at least approximately among 1mg/kg, 2.5mg/kg, 5mg/kg, 7.5mg/kg, 10mg/kg, 15mg/kg or the 20mg/kg any.In various embodiments, the effective dose of the rapamycin or derivatives thereof in the Nanoparticulate compositions of using in conjoint therapy comprises any of the following rapamycin or derivatives thereof of about 350mg/kg, 300mg/kg, 250mg/kg, 200mg/kg, 150mg/kg, 100mg/kg, 50mg/kg, 25mg/kg, 20mg/kg, 10mg/kg, 5mg/kg or 1mg/kg.

The exemplary administration frequency of the rapamycin or derivatives thereof in the Nanoparticulate compositions of using in the conjoint therapy includes but not limited to following: weekly, uninterrupted; Gave in 3 weeks in 4 weeks weekly; Per 3 weeks 1 time; Per 2 weeks 1 time; Gave in 2 weeks in 3 weeks weekly.In some embodiments, unite for 1 time in approximately per 2 weeks 1 time of the rapamycin or derivatives thereof in Nanoparticulate compositions, per 3 weeks 1 time, per 4 weeks 1 time, per 6 weeks 1 time or per 8 weeks and give.In some embodiments, give in 1 week in conjoint therapy of the rapamycin or derivatives thereof in the Nanoparticulate compositions at least about in 1 time, 2 times, 3 times, 4 times, 5 times, 6 times or 7 times (being every day) any.In some embodiments, between in conjoint therapy, giving at every turn be about June, March, January, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days at interval, below 2 days or 1 day in random time.In some embodiments, between in conjoint therapy, giving at every turn be spaced apart about January, February, March, April, May, June, August or more than the December in random time.In some embodiments, be not interrupted in the dosage regimen.In some embodiments, no more than about 1 week of interval between each administration.

The giving and can in the time period that prolongs, prolong of rapamycin or derivatives thereof in conjoint therapy in the Nanoparticulate compositions, for example from about January up to about 7 years.In some embodiments, the rapamycin or derivatives thereof in the Nanoparticulate compositions in about at least 2,3,4,5,6,7,8,9,10,11,12,18,24,30,36,48,60,72 or 84 months arbitrary during in give.In some embodiments, rapamycin or derivatives thereof Nanoparticulate compositions gives in during at least 1 month, no more than about 1 week of the interval between at every turn giving wherein, and the dosage of the rapamycin or derivatives thereof in the Nanoparticulate compositions of wherein each administration is about 0.25mg/m ²To about 75mg/m ², for example about 0.25mg/m ²To about 25mg/m ²Or about 25mg/m ²To about 50mg/m ²

In some embodiments, the dosage of the rapamycin in the Nanoparticulate compositions can be at 100-400mg/m when based on 3 all scheme administrations in the conjoint therapy ²Scope in, or when based on dosage regimen weekly at 50-250mg/m ²Scope in.Preferably, the amount of rapamycin is about 80 to about 180mg/m ²(for example about 100mg/m ²To about 150mg/m ², as about 120mg/m ²).

Other exemplary dosage regimen that Nanoparticulate compositions in the conjoint therapy (for example rapamycin/albuminous Nanoparticulate compositions) gives includes but not limited to following: 100mg/m ², weekly, be not interrupted; 75mg/m ², weekly, in 4 weeks, gave for 3 weeks; 100mg/m ², weekly, in 4 weeks, gave for 3 weeks; 125mg/m ², weekly, in 4 weeks, gave for 3 weeks; 125mg/m ², weekly, in 3 weeks, gave for 2 weeks; 130mg/m ², weekly, be not interrupted; 175mg/m ², per 2 weeks 1 time; 260mg/m ², per 2 weeks 1 time; 260mg/m ², per 3 weeks 1 time; 180-300mg/m ², per 3 weeks; 60-175mg/m ², weekly, be not interrupted; 20-150mg/m ², 2 times weekly; And 150-250mg/m ², 2 times weekly.The judgement according to the administration doctor during treating of the administration frequency of compositions can be adjusted.

Rapamycin or derivatives thereof Nanoparticulate compositions described herein can give individuality (as the people) by number of ways during conjoint therapy, parenteral for example, comprise in intravenous, intra-arterial, intraperitoneal, the lung, in the per os, suction, capsule, interior, subcutaneous, the ophthalmic of intramuscular, trachea, sheath is interior or percutaneous.For example, Nanoparticulate compositions can be by inhalation with the treatment respiratory tract disease.Rapamycin or derivatives thereof Nanoparticulate compositions can be used for the treatment of breathes for example pulmonary fibrosis of disease, bronchiolitis obliterans, pulmonary carcinoma, bronchovesicular cancer etc.In some embodiments, intravenous gives Nanoparticulate compositions.In some embodiments, per os gives Nanoparticulate compositions.

In some embodiments, the Nanoparticulate compositions of rapamycin or derivatives thereof and chemotherapeutics is according to arbitrary relieve pain of describing in table 1.

In some embodiments, method for cancer in the treatment individuality is provided, described method comprises and gives individuality: a) compositions of effective dose, described compositions comprises rapamycin or derivatives thereof and albuminous nano-particle, and b) at least a other chemotherapeutics of effective dose provides as the 1st to 53 row in the table 1.In some embodiments, the administration of Nanoparticulate compositions and chemotherapeutics can be as in the table 1 the 1st to 53 the row shown in dosage regimen in any.In some embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say except carcinoma).In some embodiments, cancer is not colon cancer (that is to say except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer.In some embodiments, one or more symptoms of cancer improve.In some embodiments, cancer is delayed or prevents.Table 1

(for example in the table 1) as used herein, RAPA are meant the compositions that comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin); GW572016 is meant Lapatinib (Lapatinib); Xel be meant capecitabine or Bevacizumab is also referred to as

Herceptin is also referred to as

Pemetrexed is also referred to as

Cetuximab is also referred to as

Gefitinib is also referred to as

FEC refers to the combination of 5-fluorouracil, epirubicin and cyclophosphamide; AC is meant that adriamycin adds the combination of cyclophosphamide.

(for example, in table 1) as used herein, AUC is meant area under curve; Q4wk is meant per 4 all administrations 1 time, and q3wk is meant per 3 all administrations 1 time; Q2wk is meant per 2 all administrations 1 time; Qwk is meant 1 administration weekly; Qwk * 3/4 is meant 1 administration weekly, gives for 3 weeks, and the 4th week did not give; Qwk * 2/3 is meant 1 administration weekly, gives for 2 weeks, and the 3rd week did not give.

In some embodiments, the invention provides the treatment method for cancer, it comprises: first therapy, it comprises the nano-particle that comprises rapamycin or derivatives thereof and carrier protein (for example albumin), with second therapy, it comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, targeted therapy, cryotherapy, ultrasound treatment and/or photodynamic therapy.In some embodiments, this method comprises: a) first therapy, and it comprises and gives the compositions that individuality comprises rapamycin and albuminous nano-particle; And b) second therapy, it comprises operation, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, targeted therapy, cryotherapy, ultrasound treatment and/or photodynamic therapy.In some embodiments, cancer can be a carcinoma of prostate.In some embodiments, second therapy is a radiotherapy.In some embodiments, second therapy is operation.

The Nanoparticulate compositions that gives the rapamycin or derivatives thereof can walk abreast before radiation and/or the operation, after radiation and/or operation or with radiation and/or operation.For example, give Nanoparticulate compositions can the radiation and/or operative therapy before or after, the interval that gives from several minutes to several weeks.In some embodiments, the time period between first therapy and second therapy makes rapamycin or derivatives thereof nano-particle and radiation and/or operation still can apply advantageously combined effect by pair cell.For example, about arbitrary time below 1,3,6,9,12,18,24,48,60,72,84,96,108,120 hour gave before the rapamycin or derivatives thereof in the Nanoparticulate compositions can and/or be performed the operation in radiation.In some embodiments, Nanoparticulate compositions gives below 9 hours about before the radiation/operation.In some embodiments, Nanoparticulate compositions about arbitrary time below 1,2,3,4,5,6,7,8,9 or 10 day before radiotherapy and/or operation gives.In some embodiments, the about arbitrary time 1,3,6,9,12,18,24,48,60,72,84,96,108 or 120 hour below of the rapamycin or derivatives thereof in the Nanoparticulate compositions after radiation and/or operation gives.In some embodiments, the extended treatment time durations is expected significantly, and wherein the interval a couple of days between two kinds of therapies is to several weeks.

The radiation (radiation) that this paper considers comprises, for example, gamma-radiation, X-ray (external beam) and directly the conveying radiosiotope to tumor cell.Also consider the DNA damage factor of other form, also be considered as microwave and UV irradiation.Can in single dose, radiate (irradiation), perhaps in the dosage splitting scheme, radiate with a series of low doses.The exit dose scope that this paper considers comprises that from about 1 to about 100Gy for example, about 5 to about 80, about 10 to about 50Gy, or about 10Gy.Accumulated dose can be used in splitting scheme.For example, scheme can comprise that cutting apart of 2Gy is individually dosed.Radioisotopic dosage range can extensively change, and depends on the type and the intensity of isotopic half-life and institute's radiation emitted.

When radiation comprises the application of radiation isotope, isotope can with targeting agent such as therapeutic antibodies coupling, it is carried to target tissue with the radioactive nucleus thuja acid.Suitable radioactive isotope includes but not limited to astatine ²¹¹, carbon ¹⁴, chromium ⁵¹, chlorine ³⁶, ferrum ⁵⁷, cobalt ⁵⁸, copper ⁶⁷, Eu ¹⁵², gallium ⁶⁷, hydrogen ³, iodine ¹²³, iodine ¹³¹, indium ¹¹¹, ferrum ⁵⁹, phosphorus ³², rhenium ¹⁸⁶, selenium ⁷⁵, sulfur ³⁵, technetium (technicium) ^99mAnd/or yttrium ⁹⁰

In some embodiments, enough radiation are applied to individuality, to such an extent as to make the normal dose of realizing the rapamycin or derivatives thereof in the required Nanoparticulate compositions of identical treatment degree reduce about at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or more in arbitrary.In some embodiments, give rapamycin or derivatives thereof in enough Nanoparticulate compositions, normal dose that make to realize the radiation that the identical treatment degree is required reduce about at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or more in arbitrary.Corresponding separately normal dose was compared all and is lowered when in some embodiments, the dosage of rapamycin or derivatives thereof in the Nanoparticulate compositions and radiation was with independent application.

In some embodiments, unite and give rapamycin or derivatives thereof Nanoparticulate compositions and radiotherapy and produce super accumulative action.In some embodiments, in the Nanoparticulate compositions rapamycin or derivatives thereof with about 50mg to 540mg or about 30mg/m ²To 300mg/m ²Dosage give once every day, and the radiation use five times every day with 80Gy.

Above being equally applicable to and radiating and/or those of the associating of performing the operation of the rapamycin or derivatives thereof Nanoparticulate compositions of uniting of disclosed and chemotherapeutics and/or hormone therapy agent.

In some embodiments, according to arbitrary dosage regimen of describing in the table 2, the Nanoparticulate compositions of rapamycin or derivatives thereof nano-particle and/or chemotherapeutics and radiation are united and are given.

In some embodiments, be provided at and treat method for cancer in the individuality, it comprises: a) first therapy, and it comprises that giving individuality comprises the compositions that contains rapamycin or derivatives thereof and albuminous nano-particle; And b) second treatment, radiation that is provided as in the 1st to 11 row in the table 2 is provided for it.In some embodiments, Nanoparticulate compositions and chemotherapeutics give can be in the table 2 the 1st to 11 the row described dosage regimen any.In some embodiments, cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.In some embodiments, cancer is a solid tumor.In some embodiments, cancer is not solid tumor (that is to say except solid tumor).In some embodiments, cancer is a plasmocytoma.In some embodiments, cancer is multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma, the brain cancer (for example glioblastoma), ovarian cancer or breast carcinoma.In some embodiments, cancer is not carcinoma (that is to say except carcinoma).In some embodiments, cancer is not colon cancer (that is to say except colon cancer).In some embodiments, cancer is not breast carcinoma (that is to say except breast carcinoma).In some embodiments, cancer is not ovarian cancer, carcinoma of prostate or the brain cancer. table 2

Rhythmicity (metronomic) therapeutic scheme

The present invention also provides the rhythmicity therapeutic scheme of arbitrary Therapeutic Method described herein and medication.Exemplary rhythmicity therapeutic scheme that the rhythmicity therapeutic scheme is used and embodiment are as discussed below and be disclosed in the United States serial of submitting on February 21st, 2,006 11/359,286--announces with U.S.'s publication No. 2006/0263434--in (for example at [0138] section to described in [0157] section those), be incorporated herein it all as a reference.In some embodiments, give Nanoparticulate compositions in during at least 1 month, interval between wherein each administration is not more than about 1 week, and the dosage of rapamycin or derivatives thereof is according to about 0.25% to about 25% of traditional its maximum tolerated dose of dosage regimen during wherein each administration.In some embodiments, give Nanoparticulate compositions in during at least 2 months, interval between wherein each administration is not more than about 1 week, and rapamycin or derivatives thereof dosage is according to about 1% to about 20% of traditional its maximum tolerated dose of dosage regimen during wherein each administration.In some embodiments, the dosage of the rapamycin or derivatives thereof of each administration is in below 25%, 24%, 23%, 22%, 20%, 18%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% any of maximum tolerated dose about.In some embodiments, Nanoparticulate compositions give weekly about at least 1 time, 2 times, 3 times, 4 times, 5 times, 6 times or in 7 times (that is every day) any.In some embodiments, the random time of the interval between each administration in less than about June, March, January, 20 days, 15 days, 12 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, below 2 days or 1 day.In some embodiments, be about January, February, March, April, May, June, August or the December random time in above at interval between each administration.In some embodiments, compositions gave in the arbitrary time durations in about at least 2,3,4,5,6,7,8,9,10,11,12,18,24,30,36,48,60,72 or 84 months.Medicament (pharmaceutical agent)

Provided herein is the compositions of using in cancer treatment method described herein, medication and dosage regimen that comprises the nano-particle that contains rapamycin.Therefore in some embodiments, rapamycin can be rapamycin or derivatives thereof or pharmaceutically acceptable salt, and the present invention considers and comprises all these embodiments.Rapamycin is called sirolimus, Lei Paming (rapammune) or Lei Paming (rapamune) sometimes in other place.The derivant of rapamycin include but not limited to be similar on the structure rapamycin or with the chemical compound of rapamycin in same total chemical classes.

In some embodiments, the derivant of rapamycin keeps and similar one or more biologies of rapamycin, pharmacology, chemistry and/or physical property (comprising for example functional).In some embodiments, rapamycin derivative has any of rapamycin active about at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.For example, in about at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% of the corresponding minimizing that preferably causes by the equal number rapamycin of the minimizing of the tumor size that causes by rapamycin derivative, cancerous cell quantity or tumor growth rate any.Exemplary rapamycin derivative comprises the benzoyl rapamycin, as disclosed in [0022] section of WO 2006/089207, is incorporated herein it all as a reference.Other exemplary rapamycin derivative comprises WY-090217, AY-22989, NSC-226080, SiiA-9268A, oxa-azepine hentriaconta-alkene (oxaazacyclohentriacontine), Tan Ximosi (CCI 779 (Wyeth)), everolimus (RAD 001 (Novartis)), pimecrolimus (ASM981), SDZ-RAD, SAR943, ABT-578, AP23573 and biological Li Mosi (Biolimus) A9.Carrier protein

Provided herein is the compositions of using in cancer treatment method described herein, medication and dosage that comprises the nano-particle that contains rapamycin and carrier protein.Therefore in some embodiments, rapamycin can be rapamycin or derivatives thereof or pharmaceutically acceptable salt, and the present invention considers and comprises all these embodiments.In some embodiments, carrier protein is an albumin.In some embodiments, carrier protein is the human serum albumin.

The proteic example of suitable carriers comprises the protein that sees usually in blood or the blood plasma, and it includes but not limited to albumin, immunoglobulin---comprise IgA, lipoprotein, apolipoprotein B, acid seromucoid, β-2-macroglobulin, Elityran, transferrins, fibronectin, factor VII, Factor IX, factors IX, factor X and analog.In some embodiments, carrier protein is non-hematoglobin protein, as casein, alpha lactalbumin and beta lactoglobulin.Carrier protein can be natural origin or synthetic preparation.In some embodiments, pharmaceutically acceptable carrier comprises albumin, as human serum albumin (HSA).The human serum albumin is the highly soluble globulin, M _r65K is made up of 585 aminoacid.HSA is rich in protein in the blood plasma, and constitutes the 70-80% of human plasma colloid osmotic pressure.The aminoacid sequence of HSA comprises 17 disulfide bond, a free mercaptan (Cys 34) and tryptophans (Trp 214) altogether.Other albumin is considered, as bovine serum albumin.These inhuman albuminous application applicable to, for example, in non-human mammal, use in the situation of these compositionss, use (comprise domestic pets and agricultural is used animal) as the veterinary.

Human serum albumin (HSA) has a plurality of hydrophobicity binding sites and (fatty acid is had 8, fatty acid is the endogenic ligand of HSA) and in conjunction with on the same group medicine not, particularly neutral and electronegative hydrophobic compound (people such as Goodman, The PharmacologicalBasis of Therapeutics, 9 ^ThEd, McGraw-Hill New York (1996)).In the subdomain HA of HSA and IIIA, two high affine binding sites have been proposed, they are the hydrophobic pockets that highly prolong, near surface has charged lysine and arginine residues, the function of performance polar ligand binding site feature (referring to, for example, people such as Fehske, Biochem.Pharmcol, 30,687-92 (1981); Vorum, Dan.Med.Bull., 46,379-99 (1999); Kragh-Hansen, Dan.Med.Bull., 1441,131-40 (1990); People such as Curry, Nat.Struct.Biol., 5,827-35 (1998); People such as Sugio, Protein.Eng., 12,439-46 (1999); People such as He, Nature, 358, people such as 209-15 (1992) and Carter., Adv.Protein.Chem., 45,153-203 (1994)).

The carrier protein in the compositions (as albumin) as the carrier of rapamycin or derivatives thereof, promptly, compare with the compositions that does not contain carrier protein, the carrier protein in the compositions makes that the rapamycin or derivatives thereof is easier and is suspended in the water-bearing media or helps to keep suspension.This can be avoided using toxic solvents and dissolve the rapamycin or derivatives thereof, gives one or more kind side effect that individuality (as the people) rapamycin or derivatives thereof causes thereby can reduce.Therefore, in some embodiments, described compositions is substantially free of (as not containing) organic solvent or surfactant.When giving the group of individuals compound, if the quantity not sufficient of organic solvent or surfactant is planted side effect, then compositions " essentially no organic solvent " or " essentially no surfactants " to cause one or more in individuality in the compositions.

If rapamycin keeps being suspended in the time of (as not having visible precipitation or sedimentation) elongated segment in the water-bearing media, as at least about the random time in 0.1,0.2,0.25,0.5,1,2,3,4,5,6,7,8,9,10,11,12,24,36,48,60 or 72 hour, then it is " stable " in aqueous suspension.Suspension is fit to give individuality (as the people) usually, but optional.The stability of suspension usually (but not must) is estimated as (as 4 ℃) under room temperature (as 20-25 ℃) or the refrigerated storage temperature under storage temperature.For example, if suspension about 15 minutes the time, does not show visible flocculation or particle aggregation for bore hole or when observing under 1000 times of optical microscopes after preparation, then suspension is stable under storage temperature.Stability also can be estimated under the accelerated test condition, as being higher than under about 40 ℃ temperature.

In some embodiments, described compositions comprises the nano-particle that contains (in various embodiments, being made up of them basically) rapamycin and carrier protein.When rapamycin was liquid form, granule or nano-particle were also referred to as drop or nano-liquid droplet.In some embodiments, rapamycin carrier protein coating.The granule of the medicament of poorly water-soluble (for example nano-particle) for example has been disclosed in U.S. Patent number 5,916,596; 6,506,405; With 6,537, in 579, also be described among U.S. Patent Application Publication No. 2005/0004002 A1.

The amount of the carrier protein in the compositions as herein described will change according to the rapamycin or derivatives thereof in the compositions and other composition.In some embodiments, the amount of the carrier protein that compositions comprises is enough to stablize rapamycin in aqueous suspension, for example, and with the form (as the stabilized nano particle suspension liquid) of stable soliquid.In some embodiments, the amount of carrier protein reduces the sedimentation velocity of rapamycin in water-bearing media.For containing particulate composition, the amount of carrier protein also depends on the size and the density of rapamycin nano-particle.

In some embodiments of either side of the present invention, rapamycin or derivatives thereof carrier protein coating, for example albumin (for example human serum albumin).In various embodiments, compositions comprises about rapamycin or derivatives thereof arbitrary more than 50%, 60%, 70%, 80%, 90%, 95% or 99% of form of nanoparticles.In some embodiments, the rapamycin or derivatives thereof constitutes by weight about arbitrary more than 50%, 60%, 70%, 80%, 90%, 95% or 99% of nano-particle.In some embodiments, nano-particle has the non-polymer matrix.In some embodiments, the rapamycin or derivatives thereof is with anhydrous, amorphous and/or amorphous form.In some embodiments, the rapamycin or derivatives thereof is unbodied.In some embodiments, nano-particle comprises the core of rapamycin or derivatives thereof, and it does not have polymeric material (for example polymeric matrix) basically.

In some embodiments, the weight ratio of albumin and rapamycin is approximately following any in nano-particle or the Nanoparticulate compositions: 18: 1 or littler, 15: 1 or littler, 14: 1 or littler, 13: 1 or littler, 12: 1 or littler, 11: 1 or littler, 10: 1 or littler, 9: 1 or littler, 8: 1 or littler, 7.5: 1 or littler, 7: 1 or littler, 6: 1 or littler, 5: 1 or littler, 4: 1 or littler or 3: 1 or littler.In some embodiments, compositions comprises the stable aqueous suspension of granule (for example nano-particle), and described granule comprises rapamycin or derivatives thereof and albumin granule (for example using the granule of the rapamycin or derivatives thereof of albumin coating).

In some embodiments, compositions (for example comprises Any shape, spherical or non-spherical form) nano-particle, its average or mid diameter is not more than about 1000 nanometers (nm), as be not more than approximately following arbitrarily: 900,800,700,600,500,400,300,200 and 100nm.In some embodiments, particulate average or mid diameter is not more than about 200nm.In some embodiments, particulate average or mid diameter is between about 20 to about 400nm.In some embodiments, particulate average or mid diameter is between about 40 to about 200nm.In some embodiments, granule is aseptic filtrable.

In some embodiments, nano-particle comprises with the rapamycin or derivatives thereof that contains carrier protein (for example albumin) coatings coating.In some embodiments, clad is made up of carrier protein basically or is made up of carrier protein.In some embodiments, at least a portion carrier protein is crosslinked (for example crosslinked by cystine linkage) in the nano-particle part of rapamycin (or rapamycin derivative) Nanoparticulate compositions.

Can there be (as freeze-dried composition) in nano-particle as herein described or be suspended in the biocompatible media with drying agent.Suitable biocompatible media includes but not limited to water, moisture buffer medium, saline, buffer saline, optional buffered Freamine, optional buffered protein solution, optional buffered sugar juice, optional buffered vitamin solution, optional buffered synthetic polymer solution, contains lipid Emulsion etc.

In some embodiments, nano-particle does not comprise the insoluble gas of blood or does not comprise the microvesicle of inflation.

The amount of the carrier protein in the compositions as herein described will change according to rapamycin or derivatives thereof in the compositions and other composition.In some embodiments, the amount of the carrier protein that compositions comprises is enough to stablize rapamycin in aqueous suspension, for example, and with the form (as the stabilized nano particle suspension liquid) of stable soliquid.In some embodiments, carrier protein is to reduce the amount of the sedimentation velocity of rapamycin in water-bearing media.The amount of carrier protein also depends on particulate size of rapamycin and density.

This paper also provides the method that reduces the side effect relevant with the medicament of administration of human poorly water-soluble, and it comprises that administration of human contains the medicament of poorly water-soluble and the pharmaceutical composition of biocompatible polymer (for example carrier protein).For example, the invention provides the method that reduces the various side effect relevant with the medicament of administration of human poorly water-soluble, various side effect include but not limited to bone marrow depression, neurotoxicity, hypersensitivity, inflammation, venous stimulation, phlebitis, pain, skin irritation (skinirritation), neutropenic heating (neutropenic fever), anaphylactic reaction, hematotoxicity and brain or neurotoxicity and their combination.In some embodiments, provide the method that reduces the hypersensitivity reaction relevant with giving the rapamycin or derivatives thereof, the hypersensitivity reaction comprises for example serious erythra, urticaria, flushing, dyspnea, tachycardia, cancer (for example lymphoma); Chest pain; Black, tar-like stool; General disease is felt, is breathed hard; Lymphadenectasis; Lose weight; Yellow-toned skin and eyes (yellow skin and eye); Stomachache; Agnogenic anxiety; Hematuria or cloudy urine; Bone pain; Feel cold; Confusion of consciousness; Faint from fear (epilepsy); Cough; The urine meaning that reduces; Hurry up, slowly or irregular heart beating; Heating; Frequent micturition; Thirsty sense increases; Inappetence; Following waist or side pain; Emotion changes; Myalgia or cramp; N or V; Numb or numb around lip, hands or the foot; The pain of urinating or difficulty; Erythra; Laryngalgia; On the lip or mouthful lumen ulcer or white dot; Hands, ankle, foot or shank swelling; Lymphadenectasis; Dyspnea; Unusual hemorrhage or injury with blood-stasis; Unusual tired or weak; Lower limb is weak or heavy, skin ulcer or the pain; Weight increase; Acne; Constipation; Diarrhoea; Move difficulty; Headache; Energy loss or weakness; Myalgia or stiff; Pain; Vibrations or tremble; Insomnia; Epistaxis; And/or face swelling.Yet these side effect only are exemplary, and other side effect relevant with rapamycin or the combination of side effect can be lowered.Side effect may be (for example a couple of days, several weeks, several months or the several years after the treatment beginning do not occur) immediately or that postpone.Antimicrobial in the compositions

In some embodiments, the present composition (for example also comprises antimicrobial (antimicrobial agent), the compositions that is used for Therapeutic Method described herein, medication and dosage, except the rapamycin or derivatives thereof, present in an amount at least sufficient to remarkable inhibition (for example postpone, reduction, slack-off and/or the prevention) the growth of microorganism amount material.The embodiment of exemplary microorganism formulation and using microbe preparation open in the United States serial of submitting on August 30th, 2,006 11/514,030 (for example at paragraph [0036] those described in [0058]).In some embodiments, antimicrobial is a chelating agen, for example EDTA, edetate, citrate, pentetic acid (pentaacetic acid, pentetate), tromethane, sorbate, Ascorbate, their derivants or their mixture.In some embodiments, antimicrobial is multiple tooth chelating agen.In some embodiments, antimicrobial is non-chelating agen, for example any in sulphite, benzoic acid, benzyl alcohol, chlorobutanol, p-Hydroxybenzoate or their derivants.In some embodiments, the antimicrobial except that rapamycin or derivatives thereof discussed above does not comprise or is used for Therapeutic Method described herein, medication and dosage.Contain sugar composite

In some embodiments, compositions of the present invention is included in the sugar of using in the Therapeutic Method described herein.In some embodiments, the present composition is included in sugar and the antimicrobial of using in the Therapeutic Method described herein.Open in the United States serial of submitting on August 30th, 2,006 11/514,030 (for example at paragraph [0084] those described in [0090]) exemplary sugar and use the embodiment of sugar.In some embodiments, sugar is as reconstruct reinforcing agent (reconstitution enhancer), and it impels dissolving or the suspension of freeze-dried composition in water and/or aqueous solution faster than the dissolving of freeze-dried composition under the situation that is not having sugar.In some embodiments, compositions is by reconstruct or liquid (for example moisture) compositions of the dry compositions acquisition that suspends again.In some embodiments, in compositions sugar concentration greater than about 50mg/ml.In some embodiments, compare with the compositions that does not have sugar, sugar is the amount that effectively increases rapamycin or derivatives thereof stability in the compositions.In some embodiments, compare with the compositions that does not have sugar, sugar is the amount that effectively improves the compositions filterability.

The sugar composite that contains described herein can also comprise one or more antimicrobials, for example at antimicrobial described herein or that describe in the United States serial of submitting on August 30th, 2,006 11/514,030.Except one or more sugar, other reconstruct reinforcing agent (for example those that describe in U.S. Patent Application Publication No. 2005/0152979 are incorporated herein it all as a reference) also can join in the compositions.In some embodiments, sugar does not comprise or is used for Therapeutic Method described herein, medication and dosage.Stabilizing agent in the compositions

In some embodiments, the present composition is also included within the stabilizing agent of using in Therapeutic Method described herein, medication and the dosage.In some embodiments, the present composition is included in antimicrobial and/or sugar and/or the stabilizing agent of using in Therapeutic Method described herein, medication and the dosage.Open in the United States serial of submitting on August 30th, 2,006 11/513,756 (for example at paragraph [0038] those described in) to [0083] and paragraph [0107] to [0114] embodiment of exemplary stabilizing agent and application stabilizing agent.The present invention provides the compositions and the method for preparation rapamycin in one of its embodiment, their keep desired therapeutic effect, and keep physics and/or chemically stable when being exposed to the dilution of temperature that some condition for example stores for a long time, raises or parenteral.Stabilizing agent comprises for example chelating agen (as citrate, malic acid, edetate or pentetate), tetrasodium pyrophosphate and gluconic acid sodium salt.In one embodiment, the invention provides the pharmaceutical preparation of the rapamycin or derivatives thereof that contains citrate, tetrasodium pyrophosphate, EDTA, gluconic acid sodium salt, citrate and sodium chloride and/or its derivant.In the another one embodiment, the invention provides the rapamycin composition that contains surfactant, the rapamycin that wherein is used to prepare preparation was anhydrous form before incorporating compositions into.

In some embodiments, stabilizing agent does not comprise or is used for Therapeutic Method described herein, medication and dosage.Pharmaceutical composition and preparation

Compositions described herein can be used in the preparation of formulation example such as pharmaceutical preparation, by implementing, to be used in Therapeutic Method described herein, medication and the dosage in conjunction with described Nanoparticulate compositions (one or more) and pharmaceutically acceptable carrier, excipient, stabilizing agent or other material known in the art.In some embodiments, pharmaceutical composition comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein (for example albumin).In some embodiments, pharmaceutical composition comprises: a) comprise the nano-particle of rapamycin or derivatives thereof and carrier protein (for example albumin), and b) at least a other therapeutic agent.In some embodiments, other therapeutic agent comprises chemotherapeutics (for example in chemotherapeutics described herein any).In some embodiments, other therapeutic agent comprises the hormone therapy agent.

In order to increase stability, can add some negative charge compositions by the negative Z electromotive force that increases nano-particle.This negative charge composition includes but not limited to: bile salt, bile acid, glycocholic acid, cholic acid, chenodeoxy cholic acid, taurocholic acid, glycochenodeoxycholate, cattle sulphur chenodeoxy cholic acid, lithocholic acid, ursodeoxycholic acid, dehydrocholic acid and other; Phospholipid; comprise the basic phospholipid of lecithin (egg yolk), it comprises following phosphatidylcholine: palmityl oleoyl phosphatidylcholine, inferior oleoyl (linoleoyl) phosphatidylcholine of palmityl, the inferior oleoyl phosphatidylcholine of stearoyl, stearoyl oleoyl phosphatidylcholine, stearoyl arachidonic phosphatidyl choline and dipalmitoyl phosphatidyl choline.Other phospholipid comprises L-α-dimyristoyl phosphatidyl choline (DMPC), dioleoyl phospholipid phatidylcholine (DOPC), distearoyl phosphatidylcholine (DSPC), hydrogenated soy phosphatidyl choline (HSPC) and other related compound.Negative charged surface activating agent or emulsifying agent also are suitable for as additive, for example, and cholesterol sulfate sodium salt (sodium cholesteryl sulfate) etc.

In some embodiments, compositions is suitable for giving the mankind.In some embodiments, compositions is suitable for giving mammal, for example under situation for animals, and domestic pets and agricultural animal.Have a variety of present compositions appropriate formulation (referring to, for example, U.S. Patent number 5,916 596 and 6,096,331, is incorporated herein it all as a reference).Following series preparation and method only are exemplary, and be restrictive anything but.Being suitable for Orally administered preparation can comprise: (a) liquid solution, the chemical compound in the diluent of being dissolved in as effective dose, diluent such as water, saline or orange juice, (b) capsule, wafer (sachets) or tablet, the active component that contains scheduled volume separately is solid or granule, (c) suspending agent in suitable liquid, (d) suitable Emulsion and (e) powder.Tablet form can comprise one or more lactose, mannitol, corn starch, potato starch, microcrystalline Cellulose, arabic gum, gelatin, silica sol, cross-linked carboxymethyl cellulose sodium, Talcum, magnesium stearate, stearic acid and other excipient, coloring agent, diluent, buffer agent, wetting agent, antiseptic, correctives and pharmaceutically compatible excipient.Lozenge form can comprise the active component in the spice that is generally sucrose and arabic gum or Tragacanth; And the pastille (pastilles) that in inert base, comprises active component, inert base such as gelatin and glycerol or sucrose and Arab, Emulsion, gel etc., except that active component, this type of excipient is known in this area.

The preparation that is suitable for parenteral comprises aqueous and non-aqueous isotonic sterile injection liquid, and it can contain antioxidant, buffer agent, antibacterial and make preparation and target receiver's the compatible solute of blood; With aqueous and non-aqueous sterile suspensions, it can contain suspending agent, solubilizing agent, thickening agent, stabilizing agent and antiseptic.Preparation may reside in the container such as ampoule (ampules) and bottle of unit dose or multiple dose sealing, and can be stored under lyophilization (lyophilizing) condition, it only need add sterile liquid excipient example (being water) at once and inject before using.Interim injection solution and suspension can be by the preparation tablets of sterilized powder, granule and aforementioned type.Preferred injectable formulation.

The preparation that is suitable for aerosol drug delivery comprises the present composition, comprises aqueous and non-aqueous isotonic sterile injection liquid, and it can contain antioxidant, buffer agent, antibacterial and solute; With aqueous and non-aqueous sterile suspensions, its can comprise independent or with the bonded suspending agent of other proper composition, solubilizing agent, thickening agent, stabilizing agent and antiseptic, they can be prepared into the aerosol that gives through sucking.These aerosols can be placed in pressurization acceptable propellant such as dichlorodifluoromethane, propane, the nitrogen etc.They also can be mixed with the medicine that is used for non-pressurised preparation, as in aerosol apparatus or in the nebulizer.

In some embodiments, compositions is configured to has about 4.5 to about 9.0 pH scope, comprise, for example, the arbitrary pH scope in about 5.0 to about 8.0, about 6.5 to about 7.5 and about 6.5 to about 7.0.In some embodiments, the pH of compositions is configured to and is not less than approximately 6, comprises, for example, is not less than in about 6.5,7 or 8 any (according to appointment 8).By adding suitable tension force improver such as glycerol, compositions and blood etc. are oozed.

Nano-particle of the present invention can be encapsulated in hard or soft capsule in, can be pressed into tablet or can mix in the diet with beverage or food fusion or by alternate manner.By mixing nano-particle and inert pharmaceutical diluent and mixture being inserted in the hard gelatin capsule of suitable size, can prepare capsule.If the expectation soft capsule, the slurry of nano-particle and acceptable vegetable oil, petroleum ether or other inert oil can be encapsulated in the gelatine capsule by machine.

The unit dosage forms that comprises compositions described herein and preparation also is provided.These unit dosage forms can be stored in the suitable packing with single unit dose or a plurality of unit dose, and can also further be sterilized and seal.For example, pharmaceutical composition (for example pharmaceutical composition of dosage or unit dosage forms) can comprise: (i) contain the nano-particle of rapamycin or derivatives thereof and carrier protein and (ii) pharmaceutically acceptable carrier.In other example, pharmaceutical composition (for example pharmaceutical composition of dosage or unit dosage forms) comprising: a) contain the nano-particle of rapamycin or derivatives thereof and carrier protein (for example albumin), and b) at least a other therapeutic agent.In some embodiments, other therapeutic agent comprises chemotherapeutics (in the chemotherapeutics for example described herein any).In some embodiments, other therapeutic agent comprises the hormone therapy agent.In some embodiments, pharmaceutical composition also comprises useful other chemical compound (or its pharmaceutically acceptable salt) of one or more treatment cancers.In various embodiments, the amount of rapamycin or derivatives thereof is included in arbitrary following ranges in the compositions: about 20 to about 50mg, about 50 to about 100mg, about 100 to about 125mg, about 125 to about 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 to about 300mg or about 300 to about 350mg.In some embodiments, the amount of rapamycin or derivatives thereof in the compositions (for example dosage or unit dosage forms) is the scope from about 54mg to about 540mg, and for example about 180mg is to the rapamycin or derivatives thereof of about 270mg or about 216mg.In some embodiments, carrier is suitable for parenteral (for example intravenous gives).In some embodiments, taxane is not included in the compositions.In some embodiments, the rapamycin or derivatives thereof is included in the only forms of pharmacologically active agents that is used for the treatment of cancer in the compositions.

In some embodiments, the present invention is a feature with the dosage form (for example unit dosage forms) that is used for the treatment of cancer, described dosage form comprises: the nano-particle that (i) comprises carrier protein and rapamycin or derivatives thereof, wherein the rapamycin or derivatives thereof amount in the unit dosage forms is to arrive in about 270mg scope and (ii) pharmaceutically acceptable carrier at about 180mg.In some embodiments, the amount of the rapamycin or derivatives thereof in the unit dosage forms comprises about 216mg.

Also be provided at the goods that comprise compositions described herein, preparation and unit dose in the suitable packing, be used for Therapeutic Method described herein, medication and dosage.Suitably being packaged in known in the art and comprising for example bottle (for example Mi Feng bottle), container (for example sealed container), ampoule, bottle, jar, flexible packaging (for example sealable polyester thin film (Mylar) or plastic bag) etc. of compositions described herein.These goods can further sterilize and/or seal.Test kit

The present invention also provides the test kit that comprises compositions described herein, preparation, unit dose and goods, is used for Therapeutic Method described herein, medication and dosage.Test kit of the present invention comprises that one or more contain the container of the Nanoparticulate compositions of rapamycin or derivatives thereof (preparation or unit dosage forms and/or goods), and in some embodiments, also comprise operation instructions according to any Therapeutic Method described herein.In some embodiments, test kit also comprises at least a other therapeutic agent.In some embodiments, other therapeutic agent comprises chemotherapeutics (any in the chemotherapeutics for example described herein).In some embodiments, other therapeutic agent comprises the hormone therapy agent.In some embodiments, test kit comprises: i) compositions, it comprises the nano-particle that contains rapamycin and carrier protein (for example albumin), ii) is used for simultaneously and/or gives nano-particle and the chemotherapeutics description with the treatment cancer in succession.In various embodiments, cancer is the cancer that early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, IV phase cancer, local advanced carcinoma, metastatic cancer, catabasis cancer, recurrence cancer, auxiliary situation cancer, auxiliary situation cancer or hormone therapy are newly resisted substantially.In various embodiments, the amount of rapamycin or derivatives thereof is included in any following ranges in the test kit: about 20 to about 50mg, about 50 to about 100mg, about 100 to about 125mg, about 125 to about 150mg, about 150 to about 175mg, about 175 to about 200mg, about 200 to about 225mg, about 225 to about 250mg, about 250 to about 300mg or about 300 to about 350mg.In some embodiments, in the test kit amount of rapamycin or derivatives thereof be from about 54mg to about 540mg scope, for example approximately 180mg to about 270mg or about 216mg.In some embodiments, test kit comprises useful one or more other chemical compounds (that is to say one or more chemical compounds except taxane) of treatment cancer.In some embodiments, other chemical compound is a chemotherapeutics.In some embodiments, other chemical compound is the hormone therapy agent.

The description that provides in the test kit of the present invention generally is label or (for example packs insert, the paper that comprises in the test kit) printed instructions on, but machine-readable description (for example, the description of carrying on disk or optical memory disc) also is an acceptable.Generally comprise the information of dosage, dosage regimen and the route of administration of relevant therapeutic interest about the description of Nanoparticulate compositions application.In some embodiments, description comprises the description that first and second therapies are provided, and wherein first or second therapy gives compositions arbitrary comprising, this combination comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein.Test kit also comprises the description to the individuality of selecting suitable treatment.

The present invention also provides the test kit that comprises compositions described herein (or unit dosage forms and/or goods) and can comprise that example is used as further described herein about the description of using the compositions method (a or many parts).In some embodiments, test kit of the present invention comprises above-mentioned packing.In other embodiments, test kit of the present invention comprise above-mentioned packing and comprise buffer agent second the packing.It can also comprise from other of commercial and User Perspective expects material, comprises other buffer agent, diluent, filter, pin, syringe and has packing insert about the indication of carrying out any method described herein.

For conjoint therapy of the present invention, test kit can contain and is useful on simultaneously and/or gives in succession the description of first and second therapies with effective treatment cancer.First and second therapies may reside in the container separately or in single container.Should be appreciated that test kit can comprise a kind of unique combination thing, or two or more compositionss, wherein a kind of compositions comprises that first therapy and a kind of chemical compound comprise second therapy.

Also can provide such test kit, it contains the rapamycin or derivatives thereof of sufficient dosage as disclosed herein, so that for individuality provides effective treatment of prolonging period, as the random time in 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer time.Test kit also can comprise rapamycin or derivatives thereof compositions, pharmaceutical composition and the preparation and the operation instructions of multiple-units dosage described herein, and to be enough to store the amount packing of using with the pharmacy, described pharmacy is the hospital pharmacy and the pharmacy of making up a prescription for example.In some embodiments, test kit comprise can reconstruct, resuspension or the rehydrated stable aqueous suspension that comprises rapamycin or derivatives thereof and albuminous nano-particle (for example using the rapamycin or derivatives thereof of albumin coating) with common formation do (for example lyophilized) compositions.

Test kit of the present invention is in the suitable packing.Suitable packing includes but not limited to bottle, bottle, jar, flexible package (for example, sealable polyester thin film or plastic bag) etc.Test kit can randomly provide other component, as buffer agent and descriptive information.The preparation method for compositions

The method that preparation contains the medicament of carrier protein and poorly water-soluble is being known in the art.For example, contain nano-particle (for example sonication, high pressure homogenizing etc.) preparation under high shear condition of the medicament and the carrier protein (for example albumin) of poorly water-soluble.These methods for example have been disclosed in, U.S. Patent number 5,916,596; 6,506,405; With 6,537, in 579, also be disclosed among U.S. Patent Publication number 2005/0004002 A1, be incorporated herein it all as a reference.

In brief, the rapamycin or derivatives thereof is dissolved in the organic solvent.Appropriate organic solvent comprises for example ketone, ester, ether, chlorinated solvent and other solvent known in the art.For example, organic solvent can be dichloromethane, chloroform/ethanol or chloroform/tert-butyl alcohol (for example have about 1: 9,1: 8,1: 7,1: 6,1: 5,1: 4,1: 3,1: 2,1: 1,2: 1,3: 1,4: 1,5: 1,6: 1,7: 1,8: 1 or 9: 1 ratio any, or have in about 3: 7,5: 7,4: 6,5: 5,6: 5,8: 5,9: 5,9.5: 5,5: 3,7: 3,6: 4 or 9.5: 0.5 any).Solution is added in the carrier protein (for example human serum albumin).Mixture stands high pressure homogenizing and (for example, uses Avestin, APV Gaulin, Microfluidizer ^TMAs come from the Microfluidizer of Microfluidics ^TMDatatron M-110EH, Stansted or Ultra Turrax homogenizer).Emulsion can circulate and arrive between about 100 circulations through high pressure homogenizer about 2, and for example about 5 arrive about 50 circulations or about 8 to about 20 circulations (for example about 8,10,12,14,16,18 or 20 circulations are arbitrary).Organic solvent can carry out evaporative removal by the suitable equipment that utilization becomes known for this purpose subsequently, and suitably include, but are not limited to can be with batch mode or with the rotary evaporator of continuous operation operation, falling film evaporator, scraper film evaporator, spray dryer etc. for equipment.The solvent removal (for example any in approximately 25mm Hg, 30mm Hg, 40mm Hg, 50mm Hg, 100mm Hg, 200mm Hg or 300mm Hg) of can reducing pressure.The time quantum that is used to remove solvent under reduced pressure can be adjusted according to the volume of preparation.For example, for the preparation with the 300mL large-scale production, solvent can remove about 5 to about 60 minutes (for example about 7,8,9,10,11,12,13,14,15,16,18,20,25 or 30 minutes random time) in about 1 to about 300mm Hg (any one among for example about 5-100mm Hg, 10-50mm Hg, 20-40mm Hg or the 25mm Hg).

If expectation, the human albumin solution can join in the dispersion to adjust the concentration of rapamycin in human serum albumin and rapamycin ratio or the adjustment dispersion.For example, human serum albumin solution (for example 25%w/v) can add to adjust human serum albumin and rapamycin ratio and arrives in about 18: 1,15: 1,14: 1,13: 1,12: 1,11: 1,10: 1,9: 1,8: 1,7.5: 1,7: 1,6: 1,5: 1,4: 1 or 3: 1 any.For example, to be added into the concentration of adjusting rapamycin in the dispersion be among 0.5mg/ml, 1.3mg/ml, 1.5mg/ml, 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml, 9mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 40mg/ml or the 50mg/ml any for human serum albumin solution (for example 25%w/v) or another solution.Dispersion can be filtered continuously by a plurality of filters, for example the combination of 1.2 μ m and 0.8/0.2 μ m filter; The for example combination of 1.2 μ m, 0.8 μ m, 0.45 μ m and 0.22 μ m filter; Or the combination of any other filter that is known in the art.The dispersion that obtains is the low-pressure refrigeration drying further.Nanoparticulate compositions can be by batch processes or continuation method (for example large-scale composition production) preparation.

If desired, second therapy (for example treating one or more useful chemical compounds of breast carcinoma), antimicrobial, sugar and/or stabilizing agent also can be included in the compositions.This other material can mix with rapamycin and/or carrier protein during rapamycin/carrier protein preparation of compositions, or adds after rapamycin/carrier protein preparation of compositions.For example, this material can add with the water-bearing media that is used for reconstruct/suspension rapamycin/carrier protein compositions, perhaps joins in the water slurry of the bonded rapamycin of carrier protein.In some embodiments, this material mixes with rapamycin/carrier protein compositions before the low-pressure refrigeration drying.In some embodiments, this material is added into the exsiccant medicament of low-pressure refrigeration/carrier protein compositions.In some embodiments, when the adding of this material changed the pH of compositions, the pH of compositions (be not must) usually was adjusted to the pH of expectation.The exemplary pH value of compositions comprises for example about 5 to about 8.5 scope.In some embodiments, the pH of compositions adjusts to and is not less than approximately 6, comprises any (for example about 8) of for example being not less than in about 6.5,7 or 8.

The present invention also provides preparation the method that is used for the treatment of the conjoint therapy of cancer as herein described.For example, by contain the compositions and second therapy (for example one or more are used for the treatment of other forms of pharmacologically active agents of cancer) of rapamycin (or derivatives thereof) and carrier protein in conjunction with (for example mixing), provide to prepare compositions the method for---it comprises rapamycin or derivatives thereof, carrier protein (for example albumin)---and second therapy.If desired, antimicrobial, sugar and/or stabilizing agent also can be included in the compositions.

Unless otherwise defined, be those of this field that the present invention belongs to technical staff common sense in the implication of all technology used herein and scientific terminology.Those skilled in the art can be appreciated that also any method and material that is similar to or is equivalent to those methods as herein described and material also can be used for practice or test the present invention.

According to the list of references that this paper quotes, description obtains the understanding of fullest.Therefore each piece of writing of the disclosure of the patent application of all publications mentioned in this article, patent, patent application and announcement all is incorporated herein by reference with it.

Provide following examples, so that explanation rather than restriction the present invention.

Embodiment

Embodiment also describes and describes in detail aspect of the present invention discussed above and embodiment, and the embodiment purpose only is example the present invention, and it should not be considered to limit by any way invention.Embodiment is not intended to represent that following experiment is all or the only experiment of being carried out.Made great efforts with guarantee about used the numeral (for example quantity, temperature etc.) accuracy, but some experimental erroies and deviation should make an explanation.Unless otherwise noted, umber is a weight portion, and molecular weight is a weight average molecular weight, and temperature is degree centigrade, and pressure is atmospheric pressure or near atmospheric pressure. Embodiment 1: form the exemplary side with rapamycin and albuminous Nanoparticulate compositions Method.

Embodiment 1-A

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein the rapamycin concentrations in the emulsifying agent is 8mg/mL, and prepares preparation on the 300mL scale.Rapamycin (2400mg) is dissolved in chloroform/tert-butyl alcohol of 12mL.Then solution is added among the human serum albumin solution (3%w/v) of 288mL.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator (Rotavap), and solvent (Hg of 25mm) under 40 ℃ of decompressions is removed rapidly.The dispersion that obtains is translucent.In this stage, the human serum albumin solution joins in the dispersion to adjust the ratio of human serum albumin and rapamycin.Dispersion continuous filtration is through a plurality of filters.Filter the big or small 85-100nm (Z of preparation _Av, Malvern Zetasizer).Described dispersion is further by lyophilizing (FTS system, Dura-Dry μ P, Stone Ridge, NewYork) 60 hours.By adding sterilized water or 0.9% (w/v) Sterile Saline, the filter cake that obtains (cake) can easily reconstitute initial dispersion.Granular size after the reconstruct is preceding identical with lyophilization.

Embodiment 1-B

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein the concentration of rapamycin is 8mg/mL in the emulsifying agent, and prepares preparation on the 200mL scale.Rapamycin (1660mg) is dissolved in the chloroform/ethanol of 8.5mL.Solution is added among the human serum albumin solution (6%w/v) of 191.5mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 25mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 85nm (Z _Av, Malvern Zetasizer).Described dispersion is further by lyophilizing (FTS system, Dura-Dry μ P, Stone Ridge, NewYork) 60 hours.By adding 0.9% (w/v) Sterile Saline, the filter cake that obtains can easily reconstitute initial dispersion.Granular size after the reconstruct is preceding identical with lyophilization.

Embodiment 1-C

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 16.2mg/mL in the emulsifying agent, and prepares preparation on the 200mL scale.Rapamycin (3240mg) is dissolved in the chloroform/ethanol of 16mL.Solution is added among the human serum albumin solution (6%w/v) of 184mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 25mm) under 40 ℃ of decompressions is removed rapidly.In this stage, the human serum albumin solution joins dispersion and makes the volume of dispersion reach 400mL, with ratio and the adjustment rapamycin concentrations of adjusting human serum albumin and rapamycin.Dispersion is by continuous filtration.0.22 the 99nm (Z of the size of the filtering preparation of μ m _Av, Malvern Zetasizer).Described dispersion is further by lyophilizing (FTS system, Dura-Dry μ P, Stone Ridge, NewYork) 60 hours.By adding 0.9% (w/v) Sterile Saline, the filter cake that obtains can easily reconstitute initial dispersion.Granular size after the reconstruct is preceding identical with lyophilization.

Embodiment 1-D

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 8.2mg/mL in the emulsifying agent, and prepares preparation on the 40mL scale.Rapamycin (328mg) is dissolved in the chloroform/ethanol of 1.8mL.Solution is added among the human serum albumin solution (6%w/v) of 38.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the 108nm (Z of the size of the filtering preparation of μ m _Av, Malvern Zetasizer).The discovery liquid suspension was stablized 48 hours at 4 ℃ and 25 ℃ at least.

Embodiment 1-E

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 8.5mg/mL in the emulsifying agent, and prepares preparation on the 30mL scale.Rapamycin (255mg) is dissolved in the chloroform/ethanol of 1.35mL.Solution is added among the human serum albumin solution (6%w/v) of 28.7mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 136nm (Z _Av, Malvern Zetasizer).The discovery liquid suspension was stablized 24 hours at 4 ℃ and 25 ℃ at least.

Embodiment 1-F

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 9.2mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (184mg) is dissolved in the chloroform/ethanol of 1.0mL.Solution is added among the human serum albumin solution (7%w/v) of 19.0mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 124nm (Z _Av, Malvern Zetasizer).The discovery liquid suspension was stablized 24 hours at 4 ℃ and 25 ℃ at least.

Embodiment 1-G

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 8.4mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (168mg) is dissolved in the chloroform/ethanol of 1.2mL.Solution is added among the human serum albumin solution (6%w/v) of 18.8mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 95nm (Z _Av, Malvern Zetasizer).

Embodiment 1-H

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 8.2mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (164mg) is dissolved in the chloroform/ethanol of 0.9mL.Solution is added among the human serum albumin solution (8%w/v) of 19.1mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 149nm (Z _Av, Malvern Zetasizer).

Embodiment 1-I

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 6.6mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (132mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (5%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 129nm (Z _Av, Malvern Zetasizer).

Embodiment 1-J

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 108nm (Z _Av, Malvern Zetasizer).

Embodiment 1-K

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (1%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion continuous filtration.0.22 the size of the filtering preparation of μ m is 99nm (Z _Av, Malvern Zetasizer).

Embodiment 1-L

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 5.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (100mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 146nm (Z _Av, Malvern Zetasizer).

Embodiment 1-M

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.The dispersion that obtains is white cream.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 129nm (Z _Av, Malvern Zetasizer).

Embodiment 1-N

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 166nm (Z _Av, Malvern Zetasizer).

Embodiment 1-O

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion continuous filtration.0.22 the size of the filtering preparation of μ m is 90nm (Z _Av, Malvern Zetasizer).

Embodiment 1-P

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination, and wherein rapamycin concentrations is 4.0mg/mL in the emulsifying agent, and prepares preparation on the 20mL scale.Rapamycin (80mg) is dissolved in the chloroform/ethanol of 0.8mL.Solution is added among the human serum albumin solution (3%w/v) of 19.2mL then.In order to form rough emulsion, 10, homogenate is 5 minutes under the 000rpm (Vitris homogenizer, model Tempest I.Q.), transfers in the high pressure homogenizer then with mixture.Under 20,000 pounds/square inch (psi), carry out emulsifying, simultaneously the recirculation emulsion.The system that obtains is transferred in the rotary evaporator, and solvent (Hg of 40mm) under 40 ℃ of decompressions is removed rapidly.Dispersion is by continuous filtration.0.22 the size of the filtering preparation of μ m is 81nm (Z _Av, Malvern Zetasizer).

Embodiment 1-Q

This embodiment explanation comprises rapamycin and albuminous preparation of drug combination.Rapamycin (30mg) is dissolved in the chloroform/ethanol of 2mL.Solution is added among the human serum albumin solution (3%w/v) of 27.0mL then.In order to form rough emulsion, mixture the following homogenate of low RPM (revolutions per minute) (Vitris homogenizer, model Tempest I.Q.) 5 minutes, is transferred in the high pressure homogenizer then.At 9000-40, carry out emulsifying under 000 pound/square inch (psi), make at least 5 circulations of emulsion recirculation simultaneously.The system that obtains is transferred in the rotary evaporator, and solvent (30mm Hg) under 40 ℃ of decompressions was removed rapidly 20-30 minute.The dispersion that obtains is translucent, and generates particulate typical mean diameter (Z in the 50-220nm scope _{On average}, Malvern Zetasizer).Described dispersion is further by lyophilizing 48 hours.By adding sterilized water or saline, the filter cake that obtains easily is reconstructed into initial dispersion.Granular size after the reconstruct is preceding identical with lyophilization.

If desired, can use the variation of these methods or these methods to prepare other compositions of the present invention (compositions that for example contains rapamycin derivative or the carrier protein except that the human serum albumin).Should be realized that the medicine of Shi Yonging, solvent and proteic amount, type and ratio are restrictive never by any way in these embodiments. The toxicology and the pharmacokinetic study of embodiment 2A:Nab-rapamycin

Come in dosage range research, to measure in (Sprague Dawley) rat the comprehensive toxicity of Nab-rapamycin in this road, pula.Under q4dx3 scheme situation, the dosage level of the Nab-rapamycin of use is 0,15,30,45,90 and 180mg/kg.Under the dosage level of 1 (N=3), 15 (N=4), 30 (N=3) and 45mg/kg (N=4), also studied the Nab-rapamycin and come pharmacokinetics in the rat in this road, pula.Before administration, after (baseline) and the administration, collect blood sample at following time point: 1,5,10,15,30 and 45 minutes, and 1,4,8,24,36 and 48 hour.Use the rapamycin of LC/MS analysed for plasma sample.

In the q4dx3 scheme, the Nab-rapamycin is nontoxic at the maximum dose level of 180mg/kg.In hematochemistry or CBC, do not observe variation.Do not observe hypercholesterolemia and hypertriglyceridemia.As illustrating in Fig. 1 and 2 C, the Nab-rapamycin demonstrates linear pharmacokinetics for dosage, and demonstrates fast that blood vessel distributes outward, as illustrated by big Vss and Vz.The C of Nab-rapamycin _MaxAnd AUC _InfWith dosage proportional (being respectively Fig. 2 A and 2B).

If desired, in measuring, these can test the toxicity and the pharmacokinetics of other compositions of the present invention (compositions that for example, contains rapamycin derivative or the carrier protein except that the human albumin). The toxicity and the pharmacokinetic study of embodiment 2B:Nab-rapamycin

Come in dosage range research, to measure in the rat comprehensive toxicity of Nab-rapamycin in this road, pula.Under the q4dx3 scheme, at the 1st, 5 and 9 day (n=20) with 0,20,40,90,120 and 180mg/kg intravenous administration Nab-rapamycin.Under the q4dx3 scheme, the Nab-rapamycin is up to 90mg/kg (540mg/m ²) dosage level fully tolerance down.In the maximum dose level of 120mg/kg and 180mg/kg, 20% and 100% mortality rate is arranged.Do not observe hypercholesterolemia and hypertriglyceridemia.

Under the dosage level of 1 (N=3), 15 (N=4), 30 (N=3) and 45mg/kg (N=4), also studied the Nab-rapamycin and come pharmacokinetics in the rat in this road, pula.Before administration, after (baseline) and the administration, collect blood sample at following time point: 1,5,10,15,30 and 45 minutes, and 1,4,8,24,36 and 48 hour.Use the rapamycin of LC/MS analysed for plasma sample.

The Nab-rapamycin demonstrates and distributes very fast mutually and big V ₂And V _SsThe C of Nab-rapamycin _MaxAnd AUC _InfProportional with dosage.Referring to Fig. 1.The PK of Nab-rapamycin is similar to Nab-paclitaxel and Nab-Ramulus et folium taxi cuspidatae terpene.Fig. 2 D has shown that intravenous administration is behind rat under 15mg/kg, 30mg/kg and 45mg/kg dosage level, and Nab-rapamycin haemoconcentration is to the log-linear figure of time. Embodiment 3: use the inhibition of Nab-rapamycin to breast cancer cell

End user's breast carcinoma (mammary carcinoma) xenograft detects the anti-tumor activity of Nab-rapamycin in mice.MX-1 tumor subcutaneous transplantation is gone into the right side and the left rib abdomen (every group of 4-5 only) of female nude mice, and makes it grow into 100mm ³Dosage level intravenous with 40mg/kg gives mice saline or Nab-rapamycin subsequently, and 3 times scheme continued for 4 weeks weekly.The administration volume is 2ml/kg.Analyze the tumor growth data by ANOVA.

The Nab-rapamycin is effective to the breast carcinoma height, and the MX-1 xenograft has been realized 88% tumor growth inhibition (contrast contrast, p＜0.0001, ANOVA; Fig. 3 A).In mice, do not observe significantly lose weight (Fig. 3 B) from the Nab-rapamycin of 40mg/kg.Therefore, Nab-rapamycin even be abundant tolerance under the 180mg/kg of q4dx3 scheme maximum dose level demonstrates linear pharmacokinetics, and effective to breast cancer model height in the body.

If desired, in this animal model, can test other compositions of the present invention (compositions that for example, contains rapamycin derivative or the carrier protein except that the human serum albumin) to measure the ability of their interior therapeutic breast carcinoma. Embodiment 4: the clinical trial of should choosing measure present composition treatment, stable, prevention and/ Or the ability of delay cancer

If desired, any compositions described herein also can be tested in the mankind, to measure described combination treatment, stable, prevention and/or to postpone the ability of cancer (for example breast carcinoma).Can use the method for standard to be used for these clinical trials.

In an illustrative methods, (for example recruit the experimenter, the health volunteer, suffer from the experimenter of cancer such as breast carcinoma, or be in the experimenter who increases cancer such as mammary cancer risk) add and use toleration, pharmacokinetics and the pharmacodynamics I phase of the Nab-rapamycin or derivatives thereof that the code test scheme carries out to study.For example, the part that can test as the present composition reaches about 250mg/m ²The rapamycin or derivatives thereof of rising dosage.Carry out the II phase subsequently, double blind random control test is to measure the effectiveness of Nab-rapamycin or derivatives thereof.If expectation, the activity of Nab-rapamycin or derivatives thereof can be compared with the activity of another treatment of cancer (for example breast carcinoma).Alternatively or additionally, another treatment of Nab-rapamycin or derivatives thereof and cancer (for example breast carcinoma) unite effectiveness can with any separately treatment effectiveness relatively. Embodiment 5: multiple myeloma (MM) cell line is in measure Nab-rapamycin activity Use

Interleukin-6 (IL-6) and insulin-like growth factor-i (IGF-1) play a crucial role in growth, existence and the drug resistance of multiple myeloma (MM) cell.And their secretions in marrow stromal cell (BMSCs) are raised owing to the adhesion of MM cell.IL-6 and IGF-1 by mitogen activated protein kinase (MAPK) and phosphatidylinositols 3 '-activation that kinases/Akt kinases (PI3-K/Akt) signal cascade amplifies regulates the growth of MM cell.Several studies show that, growth, existence, migration and the cell cycle regulating among the MM regulated in the conduction of PI3-K/Akt signal.Activatory Akt is phosphorylation downstream target molecule again, comprises the mammal target (mTOR) of forkhead transcription factor (FKHR), synthetic kinases (GSK)-3 β of glycogen and rapamycin.

MM cell line can be used in the mensuration based on cell of standard, with the ability for the treatment of MM any (for example comprising rapamycin and carrier protein such as albuminous nano-particle) of testing Nanoparticulate compositions of the present invention.Nanoparticulate compositions of the present invention is expected, because they can allow rapamycin to send and have the effect of raising with higher dosage.

For these mensuration based on cell, RPMI 8226 and U266 people MM cell line are from Rockville, and (American Type CultureCollection ATCC) obtains the American Type Culture Collection of Md.The MM cell that is derived from the patient is from patient B M sample purification, as by Y.T.Tai, and G.Teoh, Y.Shima etc., J.Immunol.Methods 235:11 is described in 2000.People MM cell line is at RPMI-1640 culture medium (Sigma Chemical, St.Louis, Mo.) cultivate in, culture medium contains 10% hyclone (FBS), 2mmol/L L-glutaminate (L-glut, GIBCO, Grand Island, N.Y.), 100 U/mL penicillins and 100mg/mL streptomycin (P/S, GIBCO).MM patient's cell is 95% CD38+, CD45RA-.Marrow stromal cell (BMSCs) is from MM patient and healthy donor's aspirate preparation, as by D.Gupta, S.Treon, Y.Shima etc. are at Lekumia, 2001 and S.Gartner and H.S.Kaplan at Proc.Nag.Acad.Sci.USA 77:4756, described in 1980.Cell is cultivated in containing the ISCOVE improvement Dulbecco culture medium of 20%FBS, 2mmol/L L-glut and 100 μ g/mL P/S.Human umbilical vein endothelial cells (HUVEC Pl 68) is from Clonetics, and Biowhittaker buys, and (Clonetics Biowhittaker) keeps in the EGM-2MV culture medium.The nano-particle that comprises rapamycin and carrier protein (for example albumin) is diluted to for example concentration in 0.01 to 100 μ M scope in culture medium. Embodiment 6: be used to measure active Drug resistance MM cell line of Nab-rapamycin and constitutional MM tumor cell group (panel)

The effectiveness of Nanoparticulate compositions of the present invention can also be assessed in Drug resistance cell line.The application of Drug resistance cell helps determining the inferior crowd of potential cancer patient, and the inferior crowd of potential cancer patient can be treated effectively by using Nanoparticulate compositions of the present invention.The activity of any (for example, comprising for example albuminous nano-particle of rapamycin and carrier protein) can use standard method to assess in one group of drug susceptibility and drug resistance people MM cell line in the Nanoparticulate compositions of the present invention.Exemplary cells system comprises dexamethasone (Dex)-sensitivity MM-1S cell line, Dex-resistance MM-1R cell line; Chemosensitive parent MM cell line RPMI-8226/S and chemoresistance subbreed RPMI-8226/Dox40 (amycin resistance) thereof, RPMI-8226/MR20 (mitoxantrone resistance) and RPMI-8226/LR5 (melphalan resistance) cell; MM-1S-TR15 is a TRAIL/Apo2L-resistance subbreed; MM-SAR-1 (being also referred to as MM-SA-1) cell, it is to come from the constitutional MM tumor cell (cell is in the resistance of external maintenance to PS-341) that proteasome inhibitor bortezomib (PS-341) is had the patient of resistance; The OCI-My-5 cell; The S6B45 cell; ARD; ARK; ARP-1; OPM-1; OPM-6; K620; LP-1; U266 and NCI-H929 cell.(Life Technologies, GrandIsland NY) cultivate all cells in RPMI 1640 culture medium that are supplemented with 10% hyclone, L-glutaminate, penicillin and streptomycin (Life Technologies).

In addition; constitutional MM tumor cell cell can separate from patient's bone marrow (BM) aspirate; this patient to conventional (based on steroid-and the cytotoxicity chemotherapy) and the anti-MM agent of developing recently (for example, thalidomide or proteasome inhibitor) resistance is arranged.Resistance constitutional MM tumor cell is collected from the patient, as above described in the embodiment 4. Embodiment 7: with the MM cell and the marrow stromal cell (BMSCs) of Nab-rapamycin treatment Co-cultivation test

When adhering to BMSCs, the MM cell has reduced the susceptiveness to conventional anti-MM therapy, conventional anti-MM therapy for example dexamethasone or cytotoxicity chemotherapeutant (Chauhan D. etc., Blood.1996,87,1104-1112).This drug resistance form is considered to accept when giving glucocorticoid and/or cytotoxicity chemotherapy key reason of its final recurrence as the patient.Therefore, any Nanoparticulate compositions of the present invention (for example, comprise rapamycin and carrier protein such as albuminous nano-particle) can be tested, whether overcome the molecule sequela of BMSCs and MM cell interaction and in this environment, realize anti-MM activity to measure them.Particularly, use MM cell and BMSCs to carry out external co-cultivation test as describing in the past.BMSCs grows to be paved with in the 24-orifice plate and (joins, confluency).After cleaning with the culture medium that does not have serum, as former description (Uchiyama H. etc., Blood 1993,82,3712-3720; Mitsiades N etc., Blood 2003,101,4055-4062), to join the BMSC-bag by hole or the control wells from the isolating primary tumor cell of MM patient (CD138+ cell greater than about 95% purity), and have or do not exist under the situation incubation 48 hours at Nanoparticulate compositions of the present invention such as Nab-rapamycin.Carry out flow cytometric analysis, detecting the CD138+ population of survival MM cell, and Nanoparticulate compositions is expressed as the percentage ratio that survivaling cell is compared with the culture of vehicle treated separately to the influence of MM cell viablity. Embodiment 8: the MTT calorimetric with the MM tissue culture cells of Nab-rapamycin treatment is deposited Live and measure

In this embodiment, estimate the influence of Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) pair cell viablity and survival.As previously described (Mitsiades C.S. etc., Blood 2001,98,795-804; Mitsiades N. etc., PNAS 2002,99,14374-14379; Mitsiades N. etc., Blood 2003,101,2377-2380), use 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT; Sigma Chemical, St Louis, cell survival is checked in Mo.) colorimetric determination.In brief, exist under the situation at 2.5% hyclone (FBS), and final concentration be the 0-100nM rapamycin Nanoparticulate compositions of the present invention (for example, comprise rapamycin and carrier protein such as albuminous nano-particle) or the DMSO vehicle Control exist under the situation, the junction with 70% to 80% with the cell bed board in 48 orifice plates.Last in each processing, cell with 1mg/mLMTT 37 ℃ of incubations 4 hours.The mixture of isopropyl alcohol and 1N HCl (23: 2, volume/volume) adds under strong imbibition situation subsequently with the dissolving first

Crystal.Become dyestuff absorbance (A) in the living cells in the 570nm measurement, 630nm is as reference wavelength.The cell viablity is estimated as the percentage ratio to the untreated control value.Test generally repeats 3 times at least, and each experimental condition generally repeats in three holes in each test at least.The report data be representative test meansigma methods+/-SD. Real Execute example 9: the propagation of using the MM cell of Nab-rapamycin treatment

In this embodiment, assessed the influence of Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) on cell proliferation and viablity.Mensuration for propagation and cell viablity, make the at first fasting 12 hours in containing the RPMI-1640 culture medium of 10% hyclone of MM cell, then (for example at Nanoparticulate compositions of the present invention, comprise rapamycin and carrier protein such as albuminous nano-particle) or DMSO contrast exist under the situation, bed board is to 96-hole microtitration plate (Costar, Cambridge, Mass.) in.By combination ³(NEN Products, Boston Mass.) measure propagation to the H-thymidine.Particularly, use ³During H-thymidine (0.5 sludge/hole (muck/well)) pulse cell 48 hours is cultivated last 6 hours, with automated cell catcher (CambridgeTechnology, Cambridge, Mass.) with cell harvesting on glass filter, and use LKB β plate (Betaplate) scintillation counter (Wallac, Gaithersburg, Md.) counting.(Promega, Madison Wis.), use MTS to measure, and carry out cell and survive force measurement to utilize CellTiter96 One Solution Reagent.Make cellular exposure in MTS, continue last 2 hours of cultivation in 48 hours, and use elisa plate reader (Molecular Devices Corp., Sunnyvale, Calif.) absorbance under the OD of measurement 570nm. Embodiment 10: the cell cycle analysis of using the MM tissue culture cells of Nab-rapamycin treatment

In this embodiment, assessed the influence of Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) cell cycle.MM cell (1 * 10 ⁶Cell) exists in Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) or DMSO contrast and cultivated under the situation 24,48 and 72 hours.Cell is used phosphate-buffered saline (PBS) to clean subsequently, is fixed and use RNAse (Sigma) processing with 70% ethanol.Cell is then with iodate third ingot (PI, 5 μ g/mL) dyeing, and (Coulter Immunology, Hialeah FIa.) upward measure the cell cycle curve at the Epics flow cytometer to use M software. Embodiment 11: use other MM cytoactive of the cell of Nab-rapamycin treatment to measure

Can further assess Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) by other determination of activity known in the art.For example, used the cracked cell cycle drafting of Caspase/PARP and quantitative, and estimated the molecule mechanism of the anti-MM activity of Nanoparticulate compositions of the present invention, but be not limited thereto by the anti-apoptotic proteins of Western blotting. The interior effect of embodiment 12A:Nab-rapamycin body to people MM cell

In this embodiment, assessed the influence of in Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as the albuminous nano-particle) body MM cell being grown.Be used in 3 * 10 among the 100mL RPMI 1640 ⁷(Mass.) subcutaneous vaccination is in the right side of mice abdomen for BectonDickinson, Bedford together with 100 μ L substrate gum base counterdie substrate (matrigel basement membrane matrix) for the MM cell.After injection the 6th day, mice was divided into two processing (treatment) group, accepts Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle), or divided to go into matched group.The processing subsequent of carrying out with Nanoparticulate compositions of the present invention is given saline by intravenous or comprises rapamycin and carrier protein such as albuminous nano-particle, and its dosage level is 40mg/kg, and 3 schemes continued for 4 weeks weekly.The administration volume is 2ml/kg.The caliper of long vertical diameter of tumor is measured and is carried out 2 times weekly to estimate gross tumor volume.When animal tumor reaches 2cm or when mice, become when dying kill animals.Evaluation is gone into the 1st day survival rate up to death from tumor injection. Embodiment 12B:Nab-rapamycin is in vivo to the effect of people MM1S cell

In this embodiment, assessed the effect that Nanoparticulate compositions of the present invention (for example, comprising rapamycin and carrier protein such as albuminous nano-particle) is grown to the MM1S cell in vivo.Be used in 3 * 10 among the 100mL RPMI 1640 ⁷(Mass.) subcutaneous vaccination is to the right side of mice abdomen for Becton Dickinson, Bedford together with 100 μ L substrate gum base counterdie substrate for the MM1S cell.After injection the 6th day, mice was divided into three processed group and accepts the Nab-rapamycin, or divided to go into matched group.Animal in matched group gives 0.9%NaCl solution (intravenous), and the animal in three processed group gives Nab-rapamycin, and dosage is 20 or 40mg/kg, and 3 times weekly, or the dosage of 30mg/kg, continue 15 days.The administration volume is 2ml/kg.The caliper of long vertical diameter of tumor is measured and is carried out 2 times weekly to estimate gross tumor volume.When animal tumor reaches 2cm or when mice, become when dying kill animals.As showing in Fig. 7, in all 3 processed group, the Nab-rapamycin is effective to the multiple myeloma height. Embodiment 13:Nab-rapamycin associating Abraxane ^TM Different to HT29 (human colon carcinoma) tumor Plant the cellular cytoxicity activity of graft

Open in the U. S. application serial number 11/359,286 that following example was submitted on February 21st, 2006 (that is, the U.S. Patent Publication of announcing on November 23rd, 2006 number 2006/0263434).Nude mice is at its right side abdomen implanted 10 ⁶Individual HT29 cell.In case tumor tangibly and at 100-200mm ³When above, begin treatment.Mice is divided into 4 groups (every group of n=8) at random.Group 1 is accepted saline, 3 times weekly, carries out for 4 weeks, intravenous; Organize the Abraxane that accepts 10mg/kg 2 every days ^TM, carried out intraperitoneal 5; The Nab-rapamycin that group 3 is accepted 40mg/kg 3 times weekly, carried out for 4 weeks, intravenous; Accept Nab-rapamycin (40mg/kg 3 times weekly, carried out for 4 weeks, intravenous injection) and Abraxane with group 4 ^TM(10mg/kg, every day carrying out intraperitoneal 5).As shown in Figure 4, Abraxane ^TMAdd the therapeutic alliance of Nab-rapamycin to the inhibition of tumor greater than arbitrary single therapy group. Embodiment 14.Nab-rapamycin is to the cell toxicant of HT29 (human colon carcinoma) tumor xenogeneic graft The property activity

Utilize HT29 human colon carcinoma xenograft to check the anti-tumor activity of Nab-rapamycin in mice.Male athymic mouse (nude mice) (3 every group) is at its right side abdomen implanted 10 ⁶Individual HT29 cell also makes it grow into about 100mm ³Mice intravenous subsequently gives the DMSO of 2mL/kg or the Nab-rapamycin of 40mg/kg dosage level, and 3 schemes continued for 4 weeks weekly, and the administration volume is 5mL/kg.Analyze the tumor growth data by ANOVA.

The Nab-rapamycin obviously suppresses the tumor growth in vivo of HT29 tumor, the HT29 tumor xenogeneic graft is reached 78.9% tumor growth inhibition (contrast contrast, p=0.005, ANOVA; Fig. 5 A).In the mice that comes from 40mg/kg Nab-rapamycin, observe-9.2% lose weight (Fig. 5 B). Embodiment 15.Nab-rapamycin is thin to HCT-116 (human colon carcinoma) tumor xenogeneic graft The cellular toxicity activity

Utilize HCT-116 human colon carcinoma xenograft to check the anti-tumor activity of Nab-rapamycin in mice.The right side abdomen of the subcutaneous implantation male nude mouse of HCT-116 tumor (10 every group) also allows make and grows into 100-221mm ³Mice is given the Nab-rapamycin of saline or 40mg/kg dosage level subsequently by intravenous, 3 schemes continued for 4 weeks weekly, and the administration volume is 10mL/kg.Analyze the tumor growth data by ANOVA.

The Nab-rapamycin obviously suppresses the tumor growth in vivo of HCT-116 tumor, the HCT-116 tumor xenogeneic graft is reached 71% tumor growth inhibition (contrast contrast, p＜0.0001, ANOVA; Fig. 6 A).Observe-9.7% and lose weight in the mice that comes from 40mg/kg Nab-rapamycin, it is similar to-10.7% of matched group lose weight (Fig. 6 B).

Claims (69)

1. method for cancer in the treatment individuality, described method comprises the compositions that gives described individual effective dose, described compositions comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein.

2. method according to claim 1, wherein said cancer are early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recur cancer, assist the situation cancer, newly assist situation cancer or the invalid substantially cancer of hormonotherapy.

3. method according to claim 1, wherein said cancer is a solid tumor.

4. method according to claim 1, wherein said cancer is a plasmocytoma.

5. method according to claim 1, wherein said cancer is selected from multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma and breast carcinoma.

6. method according to claim 1, wherein said cancer are not colon cancer.

7. method according to claim 1, one or more symptoms of wherein said cancer improve.

8. method according to claim 1, wherein said cancer is delayed.

9. method according to claim 1, wherein the amount of the described rapamycin or derivatives thereof in described effective dose compositions arrives in the scope of about 270mg at about 180mg.

10. method according to claim 9, wherein the amount of the described rapamycin or derivatives thereof in described effective dose compositions is about 216mg.

11. method according to claim 1, wherein said rapamycin or derivatives thereof is given by parenteral.

12. method according to claim 11, wherein said rapamycin or derivatives thereof intravenous gives.

13. method according to claim 1, wherein taxane is not given described individuality.

14. method according to claim 13, wherein said rapamycin or derivatives thereof are to be given unique forms of pharmacologically active agents that described individuality is used for the treatment of cancer.

15. method according to claim 1, wherein said compositions comprise the described rapamycin or derivatives thereof of about form of nanoparticles more than 50%.

16. method according to claim 1, wherein said carrier protein is an albumin.

17. method according to claim 16, wherein said albumin is the human serum albumin.

18. method according to claim 1, the average diameter of nano-particle is not more than about 200nm described in the wherein said compositions.

19. method according to claim 1, the weight ratio of carrier protein described in the wherein said Nanoparticulate compositions and described rapamycin or derivatives thereof is not more than about 18: 1.

20. method according to claim 1, wherein said individuality is the people.

21. the unit dosage forms of treatment cancer, it comprises: the nano-particle that (a) contains carrier protein and rapamycin or derivatives thereof, the amount of rapamycin or derivatives thereof described in the wherein said unit dosage forms is in about 270mg scope and (b) pharmaceutically acceptable carrier of about 180mg.

22. unit dosage forms according to claim 21, wherein the amount at rapamycin or derivatives thereof described in the described unit dosage forms is about 216mg.

23. unit dosage forms according to claim 21, wherein said carrier are suitable for parenteral and give.

24. unit dosage forms according to claim 21, wherein said carrier are suitable for intravenous and give.

25. unit dosage forms according to claim 21, there is not taxane in it.

26. unit dosage forms according to claim 21, wherein said rapamycin or derivatives thereof are the unique forms of pharmacologically active agents that is used for the treatment of cancer that contains in the described unit dosage forms.

27. unit dosage forms according to claim 21, wherein said compositions comprise the described rapamycin or derivatives thereof of about form of nanoparticles more than 50%.

28. unit dosage forms according to claim 21, wherein said carrier protein is an albumin.

29. unit dosage forms according to claim 28, wherein said albumin is the human serum albumin.

30. unit dosage forms according to claim 21, the average diameter of nano-particle is not more than about 200nm described in the wherein said compositions.

31. unit dosage forms according to claim 21, wherein the weight ratio at carrier protein described in the described Nanoparticulate compositions and described rapamycin or derivatives thereof is not more than about 18: 1.

32. test kit, it comprises: (a) nano-particle, described nano-particle comprises carrier protein and rapamycin or derivatives thereof, wherein the amount at rapamycin or derivatives thereof described in the described test kit is to use described test kit to treat the description of cancer at about 180mg in the scope of about 270mg and (b).

33. test kit according to claim 32, the amount of rapamycin or derivatives thereof described in the wherein said test kit is about 216mg.

34. test kit according to claim 32, wherein said carrier are suitable for parenteral and give.

35. test kit according to claim 34, wherein said carrier are suitable for intravenous and give.

36. test kit according to claim 32, there is not taxane in it.

37. test kit according to claim 32, the unique forms of pharmacologically active agents that be used for the treatment of cancer of wherein said rapamycin or derivatives thereof in described test kit, containing.

38. test kit according to claim 32, there is not taxane in it.

39. test kit according to claim 32, wherein said compositions comprise the described rapamycin or derivatives thereof of about form of nanoparticles more than 50%.

40. test kit according to claim 32, wherein said carrier protein is an albumin.

41. according to the described test kit of claim 40, wherein said albumin is the human serum albumin.

42. test kit according to claim 32, the average diameter of nano-particle is not more than about 200nm described in the wherein said compositions.

43. test kit according to claim 32, the weight ratio of carrier protein described in the wherein said Nanoparticulate compositions and described rapamycin or derivatives thereof is not more than about 18: 1.

44. method for cancer in the treatment individuality, described method comprises: (a) first therapy, described first therapy comprises the compositions that gives described individual effective dose, the compositions of described effective dose comprises the nano-particle that contains rapamycin or derivatives thereof and carrier protein, (b) second therapy, described second therapy is selected from chemotherapy, radiotherapy, operation, hormonotherapy, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, targeted therapy, cryotherapy, ultrasound treatment and immunotherapy.

45. according to the described method of claim 44, wherein said second therapy is a chemotherapy.

46. according to the described method of claim 45, wherein said chemotherapy comprises and gives chemotherapeutant that described chemotherapeutant is selected from antimetabolite, the medicament based on platinum, alkylating agent, tyrosine kinase inhibitor, anthracycline antibiotics, vinca alkaloids, proteasome inhibitor and topology isomerase inhibitors.

47. according to the described method of claim 45, wherein chemotherapy comprises and gives chemotherapeutant, and described chemotherapeutant is selected from: adriamycin, colchicine, cyclophosphamide, D actinomycin D, bleomycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, mitoxantrone, fluorouracil, carboplatin, carmustine (BCNU), Semustine, cisplatin, etoposide, interferon, camptothecine and derivant thereof, phenesterine, hycamtin, vinblastine, vincristine, tamoxifen, A-20968, nab-5404, nab-5800, nab-5801, Irinotecan, HKP, Ortataxel, gemcitabine, Trastuzumab, vinorelbine, Doxil, capecitabine, Alimta, Avastin, ten thousand Mactra sulcatria Deshayess, Te Luokai, Niu Lasita, Lapatinib and Sorafenib.

48. according to the described method of claim 44, wherein said second therapy is a radiotherapy.

49. according to the described method of claim 44, wherein said second therapy is operation.

50. according to the described method of claim 44, wherein said second therapy is a hormonotherapy.

51. according to the described method of claim 44, wherein said cancer is early cancer, non-metastatic cancer, primary carcinoma, advanced carcinoma, local advanced carcinoma, metastatic cancer, catabasis cancer, recurs cancer, assists the situation cancer, newly assists situation cancer or the invalid substantially cancer of hormonotherapy.

52. according to the described method of claim 44, wherein said cancer is a solid tumor.

53. according to the described method of claim 44, wherein said cancer is a plasmocytoma.

54. according to the described method of claim 44, wherein said cancer is selected from multiple myeloma, renal cell carcinoma, carcinoma of prostate, pulmonary carcinoma, melanoma and breast carcinoma.

55. according to the described method of claim 44, wherein said cancer is not a colon cancer.

56. according to the described method of claim 44, one or more symptoms of wherein said cancer improve.

57. according to the described method of claim 44, wherein said cancer is delayed.

58. according to the described method of claim 44, the amount of rapamycin or derivatives thereof described in the wherein said effective dose compositions arrives in the scope of about 270mg at about 180mg.

59. according to the described method of claim 44, the amount of rapamycin or derivatives thereof is about 216mg described in the wherein said effective dose compositions.

60. according to the described method of claim 44, wherein said rapamycin or derivatives thereof is given by parenteral.

61. according to the described method of claim 60, wherein said rapamycin or derivatives thereof intravenous gives.

62. according to the described method of claim 44, wherein taxane is not given described individuality.

63. according to the described method of claim 62, wherein said rapamycin or derivatives thereof is to give unique forms of pharmacologically active agents that described individuality is used for the treatment of cancer.

64. according to the described method of claim 44, wherein said compositions comprises the described rapamycin or derivatives thereof of about form of nanoparticles more than 50%.

65. according to the described method of claim 44, wherein said carrier protein is an albumin.

66. according to the described method of claim 65, wherein said albumin is the human serum albumin.

67. according to the described method of claim 44, wherein the average diameter at nano-particle described in the described compositions is not more than about 200nm.

68. according to the described method of claim 44, wherein the weight ratio at carrier protein described in the described Nanoparticulate compositions and described rapamycin or derivatives thereof is not more than about 18: 1.

69. according to the described method of claim 44, wherein said individuality is the people.

Images