US20100216804A1 - Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents - Google Patents
Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents Download PDFInfo
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- US20100216804A1 US20100216804A1 US12/638,297 US63829709A US2010216804A1 US 20100216804 A1 US20100216804 A1 US 20100216804A1 US 63829709 A US63829709 A US 63829709A US 2010216804 A1 US2010216804 A1 US 2010216804A1
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Definitions
- Nanoparticles for the delivery of therapeutic agents have the potential to circumvent many challenges associated with traditional delivery approaches including lack of patient compliance to prescribed therapy, adverse effects, and inferior clinical efficacy due to lack of targeted delivery.
- Important technological advantages of nanoparticles for drug delivery include the ability to deliver water-insoluble and unstable drugs, incorporation of both hydrophobic and hydrophilic therapeutic agents, and ability to utilize various routes of administration. Nanoparticle delivery systems may also facilitate targeted drug delivery and controlled release applications, enhance drug bioavailability at the site of action, reduce dosing frequency, and minimize side effects.
- nanoparticulate systems have been examined for use as drug delivery vehicles, including polymeric micelles, polymers, liposomes, low-density lipoproteins, dendrimers, hydrophilic drug-polymer complexes, and ceramic nanoparticles.
- Typical polymeric materials utilized in polymeric particulate drug delivery systems include polylactic acid (PLA), poly(D,L-glycolide) (PLG), and poly(lactide-co-glycolide) (PLGA).
- PLA and PLGA are listed as Generally Recognized as Safe (GRAS) under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are approved for use in commercially available microparticulate systems, including Decapeptyl®, Parlodel LA®, and Enantone Depot®, as well as in implant devices, such as Zoladex®.
- GRAS Generally Recognized as Safe
- nanoparticle systems such as liposomes
- polymeric nanoparticles developed to date have limited effectiveness, in part because such nanoparticles clear from the body quickly once administered and/or may accumulate in healthy tissue where treatment is not needed. Control of delivery of an active agent, using nanosystems, remains a challenge.
- biocompatible compositions capable of extended delivery of active agents, e.g., anti-neoplastic agents, that provide for prolonged and/or increased plasma drug concentrations in a patient, especially as compared to administration of an active agent alone.
- active agents e.g., anti-neoplastic agents
- a nanoparticle composition in one aspect of the invention, includes a biodegradable and/or biocompatible polymer and a therapeutic agent, wherein the biodegradable and/or biocompatible polymer matrix releases the therapeutic agent at a rate allowing controlled release of the agent over at least about 12 hours, or in some embodiments, at least about 24 hours
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a biocompatible polymer and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 12 hours when the composition is administered to a patient, and an area under the plasma concentration time curve (AUC) that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient.
- AUC area under the plasma concentration time curve
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 6 hours, at least 12 hours, or at least 24 hours or more when the composition is administered to a patient, to provide an area under the plasma concentration time curve (AUC) that is increased by at least 100%, or at least by 150%, over the AUC provided when the therapeutic agent is administered alone to a patient.
- AUC plasma concentration time curve
- disclosed nanoparticles may provide an actual peak plasma concentration (C max ) that is at least 10% higher, or even at least 100% higher, as compared to a C max of said therapeutic agent when administered alone.
- C max peak plasma concentration
- disclosed nanoparticles may provide a volume of distribution when administered to the patient that is less than or equal to about 5 plasma volumes.
- disclosed nanoparticles and/or compositions may decrease the volume of distribution (V z ) by at least 50% as compared to the V z of the patient when the therapeutic agent is administered alone.
- Biocompatible nanoparticle compositions may include long circulating nanoparticles that may further comprise a biocompatible polymer coupled to a targeting moiety, for example, a targeting moiety that is selected from the group consisting of a protein, peptide, antibody, antibody fragment, saccharide, carbohydrate, small molecule, glycan, cytokine, chemokine, nucleotide, lectin, lipid, receptor, steroid, neurotransmitter, cell surface marker, cancer antigen, or glycoprotein antigen.
- a targeting moiety may bind to prostate membrane specific antigen (PMSA).
- a disclosed nanoparticle may include a biocompatible polymer coupled to a targeting moiety, e.g., a nanoparticle may include PLA-PEG-((S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid.
- Disclosed long circulating nanoparticles may include 1 to about 4% by weight, or 2% to about 4% by weight, of a biocompatible polymer coupled to a targeting moiety
- a biocompatible nanoparticle may include a biocompatible polymer such as PLA-PEG.
- a ⁇ -hydroxy polyester-co-polyether may be polylactic acid-co-polyethylene glycol, and/or a ⁇ -hydroxy polyester-co-polyether comprises about 16 kDa polylactic acid and about 5 kDa polyethylene glycol.
- Disclosed long circulating nanoparticles may be about 80 to about 90 weight percent ⁇ -hydroxy polyester-co-polyether.
- disclosed long circulating nanoparticles may further comprise a biodegradable polymer, such as poly(lactic) acid.
- long circulating nanoparticles may have about 40 to about 50 weight percent poly(lactic)acid, and about 40 to about 50 weight percent of ⁇ -hydroxy polyester-co-polyether.
- Compositions that include such biocompatible nanoparticles and a therapeutic agent may provide a peak plasma concentration (C max ) of a therapeutic agent at least 100% higher than the C max of the therapeutic agent when administered alone, and/or the area under the plasma concentration time curve (AUC) may increased by at least 200% over the AUC of the therapeutic agent when administered alone to the patient.
- C max peak plasma concentration
- AUC area under the plasma concentration time curve
- Disclosed nanoparticle compositions may include a therapeutic agent such as one selected from the group consisting of chemotherapeutic agents, diagnostic agents, prophylactic agents, nutraceutical agents, nucleic acids, proteins, peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and combinations thereof, for example, a nanoparticle may include an anti-neoplastic agent such as docetaxel, vincristine, methotrexate, paclitaxel, or sirolimus. Disclosed nanoparticle compositions may further include an aqueous solution of a saccharide.
- a therapeutic agent such as one selected from the group consisting of chemotherapeutic agents, diagnostic agents, prophylactic agents, nutraceutical agents, nucleic acids, proteins, peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and combinations thereof
- a nanoparticle may include an anti-neo
- Also provided herein is a method of treating a solid tumor cancer, comprising administering disclosed nanoparticle composition to a patient (e.g. a mammal or primate) in need thereof.
- a patient e.g. a mammal or primate
- Such methods may provide wherein at least 24 hours after administration, a solid tumor has significant concentration of therapeutic agent.
- Contemplated herein is a method of treating a solid tumor in a mammal in need thereof, comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, a single dose of said composition may provide extended elevated plasma concentrations of said therapeutic agent in the patient for a least one day, (e.g. the peak plasma concentration (C max ) of the therapeutic agent after administration of the composition to the mammal is at least 10% higher than the C max of said therapeutic agent if administered in a non-nanoparticle formulation.)
- C max peak plasma concentration
- Also provided herein is a method of minimizing unwanted side effects or toxicity of an active agent in a patient, comprising: administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein said composition is capable of delivery a higher plasma concentration of therapeutic agent to the patient as compared to administering the therapeutic agent alone, and wherein upon administering the nanoparticle composition the volume distribution of the active agent in the patient is reduced, as compared to the volume distribution if the therapeutic agent was administered alone.
- a method for modulating the plasma concentration of a therapeutic agent in a patient e.g. a primate (e.g. human) is also provided, comprising: providing a polymeric nanoparticle comprising the therapeutic agent and administering the polymeric nanoparticle to the patient, thereby modulating the plasma concentration of the human patient.
- FIG. 1 is a schematic illustration of a nanoparticle according to one aspect of the present invention.
- FIG. 2 is a block diagram of the emulsion process used in the fabrication of nanoparticles in one aspect of the present invention.
- FIG. 3 depicts the in vitro release of docetaxel from nanoparticles and conventional docetaxel.
- FIG. 4 depicts the pharmacokinetics of docetaxel encapsulated in nanoparticles and conventional docetaxel in rats.
- FIG. 5 depicts the distribution of radioactivity determined in selected tissues of rats after IV administration of nanoparticles containing 14 C-targeting polymer ( ⁇ ), nanoparticles containing 14 C-docetaxel ( ⁇ ), and conventional 14 C -docetaxel ( ⁇ ).
- FIG. 6 depicts docetaxel concentration in tumor tissue after administration of docetaxel encapsulated in nanoparticles or conventional docetaxel to LNCaP tumor bearing SCID mice.
- FIG. 7 depicts the reduction in tumor volume in mice with PSMA-expressing LNCaP xenografts when treated with docetaxel encapsulated in nanoparticles or conventional docetaxel.
- FIG. 8 depicts pharmacokinetics of vincristine encapsulated in disclosed nanoparticles and conventional vincristine in rats.
- FIG. 9 depicts pharmacokinetics of methotrexate encapsulated in disclosed nanoparticles and conventional methotrexate in rats.
- FIG. 10 depicts pharmacokinetics of paclitaxel encapsulated in disclosed nanoparticles and conventional paclitaxel in rats.
- FIG. 11 depicts pharmacokinetics of rapamycin (sirolimus) encapsulated in disclosed nanoparticles and conventional rapamycin in rats.
- FIG. 12 depicts the tumor accumulation of docetaxel in disclosed nanoparticles in a MX-1 mouse breast tumor model.
- FIG. 13 depicts pharmacokinetics of docetaxel in a NHP model using various disclosed nanoparticles.
- the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 40%-60%.
- an “effective amount” or “therapeutically effective amount” of a composition, as used herein, is a predetermined amount calculated to achieve a desired effect.
- long-circulating refers to enhanced stability in the circulatory system of a patient, regardless of biological activity.
- nanophase and “nanosize” refer to a special state of subdivision implying that a particle has an average dimension smaller than about 1000 nm (1000 ⁇ 10 ⁇ 9 m).
- poly(ethylene glycol) or “PEG” and “poly(ethylene oxide)” or “PEO” denote polyethers comprising repeat —CH 2 —CH 2 —O— units.
- PEG and/or PEO can be different polymers depending upon end groups and molecular weights.
- poly(ethylene glycol) and PEG describes either type of polymer.
- ⁇ -hydroxy polyester refers to polymers having monomers based on one or more ⁇ -hydroxy acid, such as poly(lactic) acid, poly(glycolic) acid, poly-lactic-co-glycolic acid, polycaprolactone.
- target refers to the cell type or tissue to which enhanced delivery of the therapeutic agent is desired.
- diseased tissue may be a target for therapy.
- terapéutica agent means a compound utilized to image, impact, treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
- disclosed long-circulating nanoparticles include a therapeutic agent and biodegradable and/or biocompatible polymeric particles, optionally functionalized with targeting moieties.
- the nanoparticles are designed to circulate in a vascular compartment of a patient for an extended period of time, distribute and accumulate at a target, and release the encapsulated therapeutic agent in a controlled manner. These characteristics can result in an increased level of therapeutic agent in the target and a potential reduction in off-target exposure.
- the disclosed nanoparticles remain in circulation longer because, upon administration to a patient (e.g. a mammal, primate (e.g. human)), the disclosed nanoparticles are substantially confined to the vascular compartment of the patient, and are engineered to be cleared very slowly.
- the activity of many therapeutic agents is dependent on their pharmacokinetic behavior. This pharmacokinetic behavior defines the drug concentrations and period of time over which cells are exposed to the drug. For most therapeutics, e.g. anti-neoplastics, longer exposure times are preferred as this results in increased killing of the cancer cells.
- peak plasma concentration, or maximum plasma concentration (C max ) and area under the curve (AUC) are examples.
- AUC is a measure of plasma drug levels over time and provides an indication of the total drug exposure. Generally, plasma concentration and plasma AUC for a therapeutic agent correlate with increased therapeutic efficacy.
- a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent.
- Such compositions may provide a therapeutic effect for at least 12 hours, at least 24 hours, or at least 36 hours, or 48 hours or more, upon administration to a patient.
- peak plasma concentration (C max ) of the therapeutic agent of such nanoparticles e.g. when the composition is administered to a patient, may be least 10% higher, 20% higher, or about 10% to about 100% higher, or more, than the C max of the same therapeutic agent when administered alone.
- Actual peak plasma concentration of delivered therapeutic agent includes both agent that is released from the nanoparticle (e.g. after administration) and therapeutic agent remaining in any nanoparticle remaining in the plasma, e.g. at a given time.
- disclosed nanoparticles may provide upon administration to a patient, an area under the plasma concentration time curve (AUC), that may be increased by at least 100%, at least 200%, or about 100% to about 500% or more, over the AUC of the therapeutic agent when administered alone to the patient.
- AUC area under the plasma concentration time curve
- a provided composition that includes disclosed nanoparticles may decrease the volume of distribution (V z ) of distributed active agent, upon administration, in a patient by at least 10%, or by at least 20%, or about 10% to about 100%, as compared to the V z of the patient when the therapeutic agent is administered alone.
- a provided nanoparticle composition may provide V z in a patient that is on the same order of magnitude that the of plasma volume and/or a volume of distribution less than about 10 plasma volumes.
- a disclosed nanoparticle composition may provide a Vz that is less than, or about, 2 times the plasma volume, or less than or about 8 plasma volumes.
- a disclosed nanoparticle composition may provide a V z in a patient that is on about the same order of plasma volume, (e.g. about 5 L for an exemplary 70 kg patient), e.g. about a V z that indicates administered nanoparticles are substantially in the patient's plasma and not substantially in other tissues.
- disclosed nanoparticles may be used as a drug delivery vehicle based on the encapsulation of a therapeutic agent in a polymer matrix with controlled porosity and/or a soluble shell or matrix that upon dissolution releases the therapeutic agent in the immediate vicinity of the targeted area.
- the protection of the therapeutic agent provided by the polymer shell or matrix allows for the delivery of therapeutic agents that are water-insoluble or unstable.
- dissolution kinetics of the polymer can be designed to provide sustained release of therapeutic agents at a target for an extended period of time.
- Disclosed nanoparticles can be used for a variety of applications, such as, without limitation, drug delivery, gene therapy, medical diagnosis, and for medical therapeutics for cancer, pathogen-borne diseases, hormone-related diseases, reaction-by-products associated with organ transplants, and other abnormal cell or tissue growth.
- a patient e.g. a mammal suffering from cancer, e.g. a solid tumor cancer, prostate cancer, breast cancer or lung cancer using e.g., disclosed nanoparticles.
- contemplated diseases that may be treated using disclosed nanoparticles include a broad range of diseases and find limitation only by e.g. the therapeutic agent, the availability of a marker and/or a targeting ligand for the disease.
- a nanoparticle delivery system mitigates against colloidal instability, agglomeration, polydispersity in nanoparticle size and shape, swelling, and leakage of encapsulated materials.
- nanoparticles for delivery of therapeutic agents are provided that exhibit encapsulation efficiency.
- Encapsulation efficiency is affected by factors including, for example, material characteristics of the polymer utilized as the carrier matrix, the chemical and physical properties of the therapeutic agent to be encapsulated, and type of solvents used in the nanoparticle fabrication process.
- polymeric nanoparticles for delivery of therapeutic agents are provided that exhibit particle heterogeneity.
- Conventional polymeric nanoparticle fabrication techniques generally provide multimodal particle size distributions as a result of self-aggregation during nanoprecipitation of both the polymer and the drug molecules.
- Polymeric nanoparticles for delivery of therapeutic agents are provided, in an embodiment, that may reduce or eliminate burst release effects.
- Conventional polymeric nanoparticle carriers frequently exhibit a bimodal drug release pattern with up to about 40-80% or more of the encapsulated drug released during the first several hours. After 24 to 48 hours, drug release is significantly reduced due to the increased diffusion barrier for drug molecules located deep within the polymer matrix.
- poorly encapsulated drug molecules diffuse quickly into solution, which may lead to significant toxicity in vivo.
- the nanoparticles generally have little or no remaining therapeutic efficacy.
- polymeric nanoparticles for delivery of therapeutic agents may evade rapid capture by the reticuloendothelial system (RES), leading to extended circulation time and elevated concentration of the nanoparticles in the blood.
- Rapid capture and elimination is typically caused by the process of opsonization in which opsonin proteins present in the blood serum quickly bind to conventional nanoparticles, allowing macrophages to easily recognize and remove these particulates before they can perform their designed therapeutic function.
- the extent and nature of opsonin adsorption at the surface of nanoparticles and their simultaneous blood clearance depend on the physicochemical properties of the particles, such as size, surface charge, and surface hydrophobicity.
- a nanoparticle composition including a biodegradable and/or biocompatible polymer matrix and a therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix wherein the clearance rate of said therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix is lower than the clearance rate of said therapeutic agent when administered alone.
- methods are provided that mask or camouflage nanoparticles in order to evade uptake by the RES.
- One such method is the engineering of particles in which polyethers, such as poly(ethylene glycol) (PEG) or PEG containing surfactants, are deployed on the surface of nanoparticles.
- PEG poly(ethylene glycol)
- PEG containing surfactants are deployed on the surface of nanoparticles.
- the presence of PEG and/or PEG-containing copolymers, e.g. on the surface of nanoparticles can result in an increase in the blood circulation half-life of the nanoparticles by several orders of magnitude.
- This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.
- FIG. 1 schematically illustrates a nanoparticle according to one aspect of the present invention.
- docetaxel 100 an anti-neoplastic agent approved for the treatment of hormone refractory prostate cancer (HRPC)
- HRPC hormone refractory prostate cancer
- a matrix 110 derived from the biodegradable and/or biocompatible polymers PLA and poly(lactide-b-ethylene glycol) (PLA-PEG).
- the polymer matrix 110 contains a targeting polymer (PLA-PEG-lys(urea)glu) 120 that is end-functionalized (through the 5 amino moiety) with the lysine-urea-glutamate heterodimer (S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid (lys(urea)glu) 130 , a small molecule ligand that selectively binds to PSMA, a clinically relevant prostate cancer cell surface marker.
- a targeting polymer PDA-PEG-lys(urea)glu
- S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid lys(urea)glu
- a small molecule ligand that selectively binds to PSMA, a clinically relevant prostate cancer cell surface marker.
- the nanoparticles may be biologically degraded by, for example, enzymatic activity or cellular machinery into monomers and/or other moieties that cells can either use or excrete.
- the dissolution or degradation rate of the nanoparticles is influenced by the composition of the polymer shell or matrix.
- the half-life of the polymer (the time at which 50% of the polymer is degraded into monomers and/or other nonpolymeric moieties) may be on the order of days, weeks, months, or years, depending on the polymer.
- nanoparticle delivery characteristics such as water uptake, controlled release of therapeutic agent, and polymer degradation kinetics may be optimized through selection of polymer shell or matrix composition.
- Suitable polymers that may form some of the disclosed nanoparticles may include, but are not limited to, biodegradable ⁇ -hydroxy polyesters and biocompatible polyethers.
- exemplary polyesters include, for example, PLA, PLGA, PEG, PEO, PEGylated polymers and copolymers of lactide and glycolide (e.g., PEGylated PLA, PEGylated PGA, PEGylated PLGA), and derivatives thereof.
- suitable polymers include, for example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene inline), PEGylated poly(ethylene imine), poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[a-(4-aminobutyl)-L-glycolic acid], and combinations and derivatives thereof.
- a polymer matrix may comprise one or more acrylic polymers.
- acrylic polymers include, for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid polyacrylamide) copolymer, aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, polycyanoacrylates, and combinations thereof.
- the matrix may include dextran, acylated dextran, chitosan (e.g., acetylated to various levels), poly(vinyl) alcohol (for example, hydrolyzed to various degrees), and/or alginate, e.g. alginate complexed to bivalent cations such as a calcium alginate complex.
- dextran acylated dextran
- chitosan e.g., acetylated to various levels
- poly(vinyl) alcohol for example, hydrolyzed to various degrees
- alginate e.g. alginate complexed to bivalent cations such as a calcium alginate complex.
- Nanoparticles disclosed herein include one, two, three or more biocompatible and/or biodegradable polymers.
- a contemplated nanoparticle may include about 10 to about 99 weight percent of one or more block co-polymers that include a biodegradable polymer and polyethylene glycol, and about 0 to about 50 weight percent of a biodegradable homopolymer.
- Exemplary therapeutic nanoparticles may include about 40 to about 90 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer or about 40 to about 80 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer.
- Such poly(lactic) acid-block-poly(ethylene)glycol copolymer may include poly(lactic acid) having a number average molecular weight of about 15 to 20 kDa (or for example about 15 to about 100 kDa, e.g., about 15 to about 80 kDa), and poly(ethylene)glycol having a number average molecular weight of about 2 to about 10 kDa, for example, about 4 to about 6 kDa.
- a disclosed therapeutic nanoparticle may include about 70 to about 90 weight percent PLA-PEG and about 5 to about 25 weight percent active agent (e.g.
- PLA-PEG docetaxel
- PLA ((poly)lactic acid) may have a number average molecular weight of about 5 to about 10 kDa.
- PLGA poly lactic-co-glycolic acid
- PLA-PEG copolymers may include a chemical linker, oligomer, or polymer chain between the PLA and PEG blocks, e.g., may include PLA-linker-PEG.
- disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. about 10 weight percent docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa, e.g. about 87.5% PLA-PEG (16 kDa/5 kDa)), and optionally e.g. a PLA-PEG-lys(urea)-glu (e.g. at 2.5 weight percent).
- active agent e.g. about 10 weight percent docetaxel
- PLA-PEG with e.g. PLA about 16 kDa and PEG about 5 kDa, e.g. about 87.5% PLA-PEG (16 kDa/5 kDa)
- optionally e.g. a PLA-PEG-lys(urea)-glu e.g. at 2.5 weight percent.
- a disclosed nanoparticle which may have slow release properties, may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), (e.g. 43.25% PLA-PEG), about 42 to 45 weight percent PLA (e.g. about 75 kDa) (e.g. 43.25% PLA/75 kDa) and about 10 to 15 weight percent active agent (e.g. docetaxel).
- disclosed nanoparticles may optionally include about 1 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid (which does not include PEG, e.g a homopolymer of PLA), or may optionally include about 1 to about 50 weight percent, or about 10 to about 50 weight percent or about 30 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid.
- disclosed nanoparticles may include two polymers, e.g. PLA-PEG and PLA, in a weight ratio of about 30:60 to about 60:30, e.g, about 40:60, about 60:40, or about 50:50.
- Such substantially homopolymeric poly(lactic) or poly(lactic)-co-poly(glycolic) acid may have a weight average molecular weight of about 10 to about 130 kDa, for example, about 20 to about 30 kDa, or about 100 to about 130 kDa.
- Such homopolymeric PLA may have a number average molecule weight of about 5 to about 90 kDa, or about 5 to about 12 kDa, about 15 to about 30 kDa, or about 60 to about 90 kDa.
- Exemplary homopolymeric PLA may have a number average molecular weight of about 80 kDa or a weight average molecular weight of about 124 kDa.
- molecular weight of polymers can be related to an inherent viscosity.
- homopolymer PLA may have an inherent viscosity of about 0.2 to about 0.4, e.g. about 0.3; in other embodiments, PLA may have an inherent viscosity of about 0.6 to about 0.8.
- Exemplary PLGA may have a number average molecular weight of about 8 to about 12 kDa.
- modified surface chemistry and/or small particle size of disclosed nanoparticles may contribute to the effectiveness of the nanoparticles in the delivery of a therapeutic agent.
- nanoparticle surface charge may be modified to achieve slow biodegradation and reduce clearance of the nanoparticles.
- porosity of the polymer shell or matrix is optimized to achieve extended and controlled release of the therapeutic agent.
- the nanoparticles may have porosity in the range of about 10 to about 90 percent and/or a pore diameters in the range of about 0.001 to about 0.01 microns.
- the nanoparticles according to some embodiments of the invention may be able to penetrate the altered and often compromised vasculature of tumors via the enhanced permeability and retention (EPR) effect resulting in preferential accumulation of nanoparticles in tumor interstitium.
- EPR enhanced permeability and retention
- therapeutic agents examples include, but are not limited to, chemotherapeutic agents (e.g. anti-cancer agents), diagnostic agents (e.g. contrast agents, radionuclides, and fluorescent, luminescent, and magnetic moieties), prophylactic agents (e.g. vaccines), nutraceutical agents (e.g. vitamins and minerals), nucleic acids (e.g., siRNA, RNAi, and mircoRNA agents), proteins (e.g. antibodies), peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and/or combinations thereof.
- chemotherapeutic agents e.g. anti-cancer agents
- diagnostic agents e.g. contrast agents, radionuclides, and fluorescent, luminescent, and magnetic moieties
- prophylactic agents e.g. vaccines
- nutraceutical agents e.g. vitamins and minerals
- nucleic acids e.g., siRNA, RNAi, and mircoRNA agents
- the active agent or drug may be a therapeutic agent such as an antineoplastic such as a mTor inhibitor (e.g., sirolimus (rapamycin), temsirolimus, or everolimus), vinca alkaloids such as vincristine, a diterpene derivative, a taxane such as paclitaxel (or its derivatives such as DHA-paclitaxel or PG-paxlitaxel), docetaxel, or methatrexate.
- antineoplastic such as a mTor inhibitor (e.g., sirolimus (rapamycin), temsirolimus, or everolimus), vinca alkaloids such as vincristine, a diterpene derivative, a taxane such as paclitaxel (or its derivatives such as DHA-paclitaxel or PG-paxlitaxel), docetaxel, or methatrexate.
- a mTor inhibitor e.g., siroli
- the therapeutic agent to be delivered is an agent useful in the treatment of cancer (e.g., a solid tumor cancer e.g., prostate or breast cancer).
- Such therapeutic agents may include, for example, doxorubicin (adriamycin), gemcitabine (gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere), mitoxantrone, mitoxantrone hydrochloride, aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-I1, 1O-hydroxy-7-ethylcamptothecin (SN38), dacarbazine, S-I capecitabine, ftorafur, 5′de
- contemplated nanoparticles may include more than one therapeutic agent. Such nanoparticles may be useful, for example, in aspects where it is desirable to monitor a targeting moiety as such moiety directs a nanoparticle containing a drug to a particular target in a subject.
- Disclosed nanoparticles may be formed using an emulsion process, e.g. as presented as a block diagram in FIG. 2 .
- an organic polymer/drug solution containing docetaxel, PLA, PLA-PEG, and PLA-PEG-lys(urea)glu dissolved in a co-solvent mixture of ethyl acetate and benzyl alcohol is dispersed in an aqueous solution of sodium cholate, ethyl acetate, and benzyl alcohol to form a coarse emulsion.
- the conditions under which the emulsion process is performed favor the orientation of the PEG and/or PEG-lys(urea)glu polymer chains toward the particle surface.
- an orientation is achieved where the PEG is folded within the nanoparticle polymer shell or matrix.
- a coarse emulsion can be passed through a high pressure homogenizer to reduce the droplet size, forming a fine emulsion.
- the fine emulsion is diluted into an excess volume of a quench solution of cold water containing polysorbate 80.
- the presence of polysorbate 80 serves to remove excess therapeutic agent that has not been encapsulated in the nanoparticle.
- polysorbate 80 may also be adhered or associated with a nanoparticle surfaces. While not wishing to be bound by theory, polysorbate 80 coupled to the nanoparticle surfaces may impact characteristics such as controlled release of therapeutic agent and polymer degradation kinetics.
- Quenching may be performed at least partially at a temperature of about 5° C. or less.
- water used in the quenching may be at a temperature that is less that room temperature (e.g., about 0 to about 10° C., or about 0 to about 5° C.).
- not all of the therapeutic agent e.g., docetaxel
- a drug solubilizer is added to the quenched phase to form a solubilized phase.
- the drug solubilizer may be for example, Tween 80, Tween 20, polyvinyl pyrrolidone, cyclodextran, sodium dodecyl sulfate, or sodium cholate.
- Tween-80 may added to the quenched nanoparticle suspension to solubilize the free drug and prevent the formation of drug crystals.
- a ratio of drug solubilizer to therapeutic agent e.g., docetaxel
- a ratio of drug solubilizer to therapeutic agent is about 100:1 to about 10:1.
- Ethyl acetate and benzyl alcohol are extracted from the organic phase droplets, resulting in formation of a hardened nanoparticle suspension.
- docetaxel or other active agent may be encapsulated at e.g. a loading level of 10% w/w; corresponding to more than 10,000 drug molecules per nanoparticle.
- the nanoparticle suspension is processed using tangential flow ultrafiltration/diafiltration (UF/DF) with cold water to remove processing aids and to concentrate the nanoparticles to a desired value. Residual precursor materials and excess organics present in unwashed nanoparticle suspensions may have a detrimental impact on biomedical applications as well as undesired toxic effects on the physiological system.
- the washed nanoparticle suspension is then passed through a prefilter and at least two sterilizing-grade filters.
- the nanoparticles may be combined with an acceptable carrier to produce a pharmaceutical formulation, according to another aspect of the invention.
- the carrier may be selected based on factors including, but not limited to, the route of administration, the location of the targeted disease tissue, the therapeutic agent being delivered, and/or the time course of delivery of the therapeutic agent.
- a concentrated sucrose solution is aseptically added to the sterile nanoparticle suspension to produce a pharmaceutical formulation.
- the sucrose serves as a cryoprotectant and a tonicity agent.
- the resulting pharmaceutical formulation is a sterile, aqueous, injectable suspension of docetaxel encapsulated in nanoparticles comprised of biocompatible and biodegradable polymers.
- the suspension is assayed for docetaxel content, and may be aseptically diluted to the desired concentration.
- the particle suspension is aseptically filled and sealed in glass vials.
- the bulk drug product suspension is stored frozen at ⁇ 20° C. ⁇ 5° C. prior to filling into vials.
- nanoparticles of the invention may be modified in some embodiments to achieve desired drug-delivery features.
- nanoparticle characteristics such as surface functionality, surface charge, particle size, zeta ( ⁇ ) potential, hydrophobicity, controlled release capability, and ability to control immunogenicity, and the like, may be optimized for the effective delivery of a variety of therapeutic agents.
- the long-circulating nanoparticles produced according to the emulsion process shown in FIG. 2 are well dispersed and unagglomerated, which facilitates conjugation or functionalization of the nanoparticle surfaces with targeting moieties.
- Disclosed nanoparticles may include optional targeting moieties, which may be selected to ensure that the nanoparticles selectively attach to, or otherwise associate with, a selected marker or target.
- disclosed nanoparticles may be functionalized with an amount of targeting moiety effective for the treatment of prostate cancer in a subject (e.g., a low-molecular weight PSMA ligand).
- an amount of targeting moiety effective for the treatment of prostate cancer in a subject e.g., a low-molecular weight PSMA ligand.
- targeting moieties effective for the treatment of prostate cancer in a subject
- the nanoparticles are effective only at targeted sites, which minimizes adverse side effects and improves efficacy.
- Targeted delivery also allows for the administration of a lower dose of therapeutic agent, which may reduce undesirable side effects commonly associated with traditional treatments of disease.
- disclosed nanoparticles may be optimized with a specific density of targeting moieties on the nanoparticle surface, such that e.g., an effective amount of targeting moiety is associated with the nanoparticle for delivery of a therapeutic agent.
- the fraction of the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety may be less than 80% of the total.
- the fraction of the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety is less than about 50% of the total.
- Increased density of the targeting moiety may, in some embodiments, increase target binding (cell binding/target uptake).
- targeting moieties include, for example, proteins, peptides, antibodies, antibody fragments, saccharides, carbohydrates, glycans, cytokines, chemokines, nucleotides, lectins, lipids, receptors, steroids, neurotransmitters and combinations thereof.
- markers that may be useful in embodiments of the invention include, but are not limited to, cell surface markers, a cancer antigen (CA), a glycoprotein antigen, a melanoma associated antigen (MAA), a proteolytic enzyme, an angiogenesis marker, a prostate membrane specific antigen (PMSA), a small cell lung carcinoma antigen (SCLCA), a hormone receptor, a tumor suppressor gene antigen, a cell cycle regulator antigen, a proliferation marker, and a human carcinoma antigen.
- exemplary targeting moieties include:
- a disclosed nanoparticle may include PLA-PEG-targeting moiety, e.g. S,S-2- ⁇ 3-[1-carboxy-5-amino-pentyl]-ureido ⁇ -pentanedioic acid.
- disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), and about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16 kDa/5 kDa PLA-PEG).
- a disclosed nanoparticle may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa) about 42 to 45 weight percent PLA (e.g. about 75 kDa), about 10 to 15 weight percent active agent (e.g. docetaxel), and about about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16/5 PLA-PEG).
- PLA-PEG with e.g. PLA about 16 kDa and PEG about 5 kDa
- PLA e.g. about 75 kDa
- active agent e.g. docetaxel
- PLA-PEG-lys(urea)glu 16/5 PLA-PEG
- targeting moieties are targeted to an antigen associated with a disease of a patient's immune system or a pathogen-borne condition.
- targeting moieties are targeted to cells present in normal healthy conditions. Such targeting moieties may be directly targeted to a molecule or other target or indirectly targeted to a molecule or other target associated with a biological molecular pathway related to a condition.
- the amount of nanoparticles administered to a patient may vary and may depend on the size, age, and health of the patient, the therapeutic agent to be delivered, the disease being treated, and the location of diseased tissue. Moreover, the dosage may vary depending on the mode of administration.
- the nanoparticles are administered to a subject systemically.
- methods of administration may include, but are not limited to, intravascular injection, intravenous injection, intraperitoneal injection, subcutaneous injection, and intramuscular injection.
- the nanoparticles necessitate only a single or very few treatment sessions to provide effective treatment of disease, which ultimately may facilitate patient compliance.
- administration of the nanoparticles can occur via intravenous infusion once every three weeks.
- a patient e.g. a mammal in need thereof.
- the solid tumor may have significant concentration of therapeutic agent, e.g. may have an increase in tumor drug concentration of at least about 20%, or at least about 30% or more active agent (e.g. docetaxel) as compared to the amount present in a tumor after administration of (e.g. the same dosage) of therapeutic agent alone (e.g. not in a disclosed nanoparticle composition).
- a method of treating a solid tumor in a mammal comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a ⁇ -hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, wherein single dose of said composition provides extended release of said therapeutic agent for a least one day.
- Such methods may provide an actual peak plasma concentration (C max ) of the therapeutic agent after administration of the composition to the mammal that is at least 10% higher, or at least 20% higher or 100% higher or more than the C max of said therapeutic agent if administered in a non-nanoparticle formulation.
- Disclosed methods may provide, upon administration of nanoparticles, an area under the plasma concentration time curve (AUC) in a patient that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient.
- disclosed methods may also, alone or in addition to the above plasma parameters, decrease the volume of distribution (V z ) of the therapeutic agent upon administration by at least 50% as compared to the V z of the patient when the therapeutic agent is administered alone.
- disclosed nanoparticles may, upon administration, provide a higher plasma concentration of therapeutic agent as compared to administering an equivalent dosage of therapeutic agent alone.
- disclosed nanoparticles may circulate substantially in the vascular compartment, and therefore may not contribute significantly to other areas that may cause toxicity or unwanted side effects.
- a suspension of docetaxel encapsulated in nanoparticles fabricated according to the emulsion process depicted in FIG. 2 and Example 12 using 87.5 weight percent PLA-PEG, 10 wt. % docetaxel, and 2.5 wt. percent docetaxel (Formulation A) (all docetaxel nanoparticle formulations used in these Examples were in a composition of 5% nanoparticles, 65% water, and 30% sucrose). was placed in a dialysis cassette and incubated in a reservoir of phosphate buffered saline (PBS) at 37° C. with stirring. Samples of the dialysate were collected and analyzed for docetaxel using reversed phase high performance liquid chromatography (HPLC). For comparison, conventional docetaxel was analyzed under the same procedure.
- PBS phosphate buffered saline
- FIG. 3 presents the in vitro release profile of docetaxel encapsulated in nanoparticles compared to conventional docetaxel. Release of the encapsulated docetaxel from the polymer matrix was essentially linear over the first 24 hours with the remainder gradually released over a period of about 96 hours.
- FIG. 4 and Example Table 2.1 present the observed pharmacokinetic profiles and pharmacokinetic parameters, respectively, of docetaxel encapsulated in nanoparticles and conventional docetaxel.
- Example Table 2.1 further includes data from the preclinical development of TAXOTERE® for comparative reference (Bissery et al. 1995). The results for conventional docetaxel were consistent with those reported in literature (Bissery et al. 1995), indicating docetaxel was rapidly cleared from the blood and distributed to tissues. The peak plasma concentration (C max ) was observed at the first sampling time point for all treatments.
- the C max and AUC of the docetaxel encapsulated in nanoparticles were approximately 100 times higher than that for conventional docetaxel. The difference in the C max may be attributable to having missed the rapid initial tissue distribution phase for conventional docetaxel.
- the data indicate that the docetaxel encapsulated in nanoparticles largely remains in circulation upon injection and is slowly cleared over a 24 hour period. The data further shows that docetaxel is released from the nanoparticles in a controlled manner during the 24 hour period (e.g., rapid burst release is not observed). If the nanoparticles were very quickly cleared from circulation, the large increase in AUC would not be observed. Similarly, if there was rapid burst release of docetaxel from the nanoparticles, the pharmacokinetic profile would be expected to more closely resemble that of conventional docetaxel.
- Blood was drawn at 1, 3, 6, 12, and 24 hours post-dosing and processed to plasma. Immediately following blood collection, the rats were euthanized by CO 2 asphyxiation and tissues were immediately collected, blotted, weighed, and frozen on dry ice. Tissue samples were stored frozen (approximately ⁇ 70° C.) until analysis for radioactivity by liquid scintillation (LS) counting.
- LS liquid scintillation
- the docetaxel encapsulated in nanoparticles was gradually cleared from the plasma, exhibiting an approximate 2-fold decrease in plasma concentration over the 24 hour period studied.
- MPS mononuclear phagocyte system
- this difference in plasma clearance times may be attributed to certain nanoparticle characteristics, including particle size and surface properties (e.g., surface charge and porosity).
- the profiles of the docetaxel encapsulated in nanoparticles wherein the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14 C-labeled and the docetaxel encapsulated in nanoparticles wherein the encapsulated docetaxel was 14 C-labeled would be superimposable.
- Example Tables 3.1, 3.2, and 3.3 present the tissue distribution of radioactivity determined in rats after intravenous (IV) administration of (1) docetaxel encapsulated in nanoparticles in which the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14 C-labeled, (2) docetaxel encapsulated in nanoparticles in which the encapsulated docetaxel was 14 C-labeled, and (3) 14 C-labeled conventional docetaxel, respectively.
- Example FIG. 5 contains the radioactivity concentration curves of the test articles determined in plasma, liver, spleen, and bone marrow.
- the concentration of docetaxel encapsulated in nanoparticles was higher in most tissues than conventional docetaxel.
- concentration of docetaxel derived from the nanoparticles was lower than or approximately the same as the concentration of conventional docetaxel in all of the tissues evaluated, except the spleen.
- the concentration of docetaxel encapsulated in nanoparticles was higher than conventional docetaxel at early timepoints and throughout the 24 hour period in the spleen, the nanoparticles doped with docetaxel were well tolerated at approximately 10 mg/kg docetaxel dose.
- body weight changes and clinical observations in the Sprague-Dawley rats indicate that the docetaxel encapsulated in nanoparticles was tolerated as well as conventional docetaxel through a range of acute doses (5-30 mg/kg docetaxel).
- mice Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 300 mm 3 . At this time, a single intravenous (IV) dose of 50 mg/kg docetaxel was administered as either docetaxel encapsulated in nanoparticles or conventional docetaxel. The test subjects were sacrificed 2 hour or 12 hour post-dose. The tumors from each group were excised and assayed for docetaxel using liquid chromatography-mass spectrometry (LC-MS).
- IV intravenous
- Example Table 4.1 and FIG. 6 The measured docetaxel concentrations in tumors excised from the test subjects dosed with docetaxel encapsulated in nanoparticles or conventional docetaxel are presented in Example Table 4.1 and FIG. 6 .
- the tumor docetaxel concentration in test subjects receiving docetaxel encapsulated in nanoparticles was approximately 7 times higher than in the test subjects receiving conventional docetaxel.
- mice Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 250 mm 3 . Subsequently, the mice were treated every other day (Q2D) for four doses, with an eight day holiday, followed by another four doses at the Q2D schedule.
- Q2D every other day
- Example FIG. 7 Average tumor volumes for each treatment group are shown in Example FIG. 7 .
- Treatment with either conventional docetaxel or docetaxel encapsulated in nanoparticles resulted in appreciable reduction in tumor volume.
- Tumor volume reduction was greater in test subjects receiving docetaxel encapsulated in nanoparticles compared to conventional docetaxel.
- Nasal and eye discharges appeared with a pattern that was unrelated to dose level, test article, sex of the animals, or time after dosing, and this clinical sign was considered to be possibly related to docetaxel and/or to stress from the dosing procedure.
- Example Table 6.1 male and female rats dosed with either conventional docetaxel or docetaxel encapsulated in nanoparticles showed generally minor deficits in body weight gain or actual body weight losses that were considered to be due to docetaxel toxicity.
- the no-adverse effect level (NOAEL) of nanoparticles doped with docetaxel in this study was considered to be 7.5 mg/kg.
- rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 14 having vincristine and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or vincristine alone.
- the release profiles are shown in FIG. 8 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with vincristine alone is as follows:
- rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 15 having methotrexate and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or methotrexate alone.
- the release profiles are shown in FIG. 9 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with methotrexate alone is as follows:
- rats were intravenously dosed with 1.0 mg/kg with either nanoparticles prepared as in FIG. 2 having paclitaxel and PLA-PEG (formulation C) and no specific targeting moiety (passively targeted nanoparticles (PTNP); or paclitaxel alone.
- the release profiles are shown in FIG. 10 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with paclitaxel alone is as follows:
- rats were intravenously dosed with 2.0 mg/kg with either nanoparticles prepared as in FIG. 2 and Example 16, having rapamycin and PLA-PEG and no specific targeting moiety (passively targeted nanoparticles (PTNP); or rapamycin alone.
- the release profiles are shown in FIG. 11 .
- Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software.
- a comparison of the pharmacokinetics of the nanoparticles with rapamcyin alone is as follows:
- mice with MX-1 breast tumors were randomized into three groups, receiving docetaxel (3 mice), passively targeted nanoparticles (Formulation A, without a targeting moiety, PTNP), or Formulation A.
- the average tumor mass was 1.7 g (RSD 34%).
- Mice were then injected with 10 mg/kg of the test article, then euthanized 24 hours later and the tumors were removed and analyzed for docetaxel content using LC/MS/MS. Results are depicted in FIG. 12 .
- the percent of injected dose in the tumor was 3% (for docetaxel alone), 30% for PTNP, and 30% Formulation A.
- the dosing day was 1 day and the formulations were administered by 30 minute IV infusion at 25 mg/m 2 docetaxel or 50 mg/m 2 docetaxel (animals were randomized and then dosed with 50 mg/m2 on day 29 and PK, hematology and clinical chemistry were measured for 21 days). At the end of the study, PK, hematology and clinical chemistry collected over a 21 day period were assessed.
- FIG. 12 depicts the results of male (M) and female (F) PNP.
- a comparison of the pharmacokinetics of the nanoparticles of Formulation A (25 mg/m 2 dose) with docetaxel alone is as follows:
- An organic phase is formed composed of a mixture of docetaxel (DTXL) and polymer (homopolymer, co-polymer, and co-polymer with ligand).
- the organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent.
- aqueous phase is composed of a surfactant and some dissolved solvent.
- about 30% solids in the organic phase is used.
- the primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer.
- the rotor/stator yielded a homogeneous milky solution, while the stir bar produced a visibly larger coarse emulsion. It was observed that the stir bar method resulted in significant oil phase droplets adhering to the side of the feed vessel, suggesting that while the coarse emulsion size is not a process parameter critical to quality, it should be made suitably fine in order to prevent yield loss or phase separation. Therefore the rotor stator is used as the standard method of coarse emulsion formation, although a high speed mixer may be suitable at a larger scale.
- the primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer.
- Organic phase was emulsified 5:1 O:W with standard aqueous phase, and multiple discreet passes were performed, quenching a small portion of emulsion after each pass.
- the indicated scale represents the total solids of the formulation.
- FIGS. 8 and 9 depicts the effect of solids concentration on particle size and drug loading; with the exception of the 15-175 series, all batches are placebo. For placebo batches the value for % solids represents the % solids were drug present at the standard 20% w/w.
- Table A summarizes the emulsification process parameters.
- the fine emulsion is then quenched by addition to deionized water at a given temperature under mixing.
- the emulsion is added to a cold aqueous quench under agitation. This serves to extract a significant portion of the oil phase solvents, effectively hardening the nanoparticles for downstream filtration. Chilling the quench significantly improved drug encapsulation.
- the quench:emulsion ratio is approximately 5:1.
- Tween 80 A solution of 35% (wt %) of Tween 80 is added to the quench to achieve approximately 2% Tween 80 overall After the emulsion is quenched a solution of Tween-80 is added which acts as a drug solubilizer, allowing for effective removal of unencapsulated drug during filtration. Table B indicates each of the quench process parameters.
- the temperature must remain cold enough with a dilute enough suspension (low enough concentration of solvents) to remain below the T g of the particles. If the Q:E ratio is not high enough, then the higher concentration of solvent plasticizes the particles and allows for drug leakage. Conversely, colder temperatures allow for high drug encapsulation at low Q:E ratios (to ⁇ 3:1), making it possible to run the process more efficiently.
- the nanoparticles are then isolated through a tangential flow filtration process to concentrate the nanoparticle suspension and buffer exchange the solvents, free drug, and drug solubilizer from the quench solution into water.
- a regenerated cellulose membrane is used with with a molecular weight cutoffs (MWCO) of 300.
- a constant volume diafiltration (DF) is performed to remove the quench solvents, free drug and Tween-80.
- DF constant volume diafiltration
- buffer is added to the retentate vessel at the same rate the filtrate is removed.
- Crossflow rate refers to the rate of the solution flow through the feed channels and across the membrane. This flow provides the force to sweep away molecules that can foul the membrane and restrict filtrate flow.
- the transmembrane pressure is the force that drives the permeable molecules through the membrane.
- the filtered nanoparticle slurry is then thermal cycled to an elevated temperature during workup.
- a small portion typically 5-10% of the encapsulated drug is released from the nanoparticles very quickly after its first exposure to 25° C.
- ‘loosely encapsulated’ drug can be removed and improve the product stability at the expense of a small drop in drug loading.
- the nanoparticle suspension (concentration 50 mg/ml), is passed through a sterilizing grade filter (0.2 ⁇ m absolute).
- Pre-filters are used to protect the sterilizing grade filter in order to use a reasonable filtration area/time for the process. Filtration flow rate is ⁇ 1.3 L/min/m 2 .
- the filtration train is Ertel Alsop Micromedia XL depth filter M953P membrane (0.2 ⁇ m Nominal); Pall SUPRAcap with Seitz EKSP depth filter media (0.1-0.3 ⁇ m Nominal); Pall Life Sciences Supor EKV 0.65/0.2 micron sterilizing grade PES filter. 0.2 m 2 of filtration surface area per kg of nanoparticles for depth filters and 1.3 m 2 of filtration surface area per kg of nanoparticles for the sterilizing grade filters can be used.
- the nanoparticle preparation protocol described in Example 12 was modified to produce slow release nanoparticles.
- a batch of nanoparticles was produced that incorporated a 50:50 ratio of 100 DL 7E PLA (see Table 1) with the 16/5 PLA-PEG copolymer.
- the addition of high molecular weight PLA is thought to decrease drug diffusion by increasing crystallinity, raising the glass transition temperature, or reducing drug solubility in the polymer.
- Nanoparticle batches were prepared using the general procedure of Example 12, with 80% (w/w) Polymer-PEG or Polymer-PEG with homopolymer PLA at 40% (w/w) each, with a batch of % total solids of 5%, 15% and 30%. Solvents used were: 21% benzyl alcohol and 79% ethyl acetate (w/w). For each 2 gram batch size, 400 mg of drug was used and 1.6 g of 16-5 Polymer-PEG or 0.8 g of 16-5 Polymer-PEG+0.8 g of 10 kDa PLA (homopolymer) was used.
- the organic phase (drug and polymer) is prepared in 2 g batches: To 20 mL scintillation vial add drug and polymer(s). The mass of solvents needed at % solids concentration is:: 5% solids: 7.98 g benzyl alcohol+30.02 g ethyl acetate; 30% solids: 0.98 g benzyl alcohol+3.69 g ethyl acetate
- An aqueous solution is prepared with 0.5% sodium cholate, 2% benzyl alcohol, and 4% ethyl acetate in water. Add to the bottle 7.5 g sodium cholate, 1402.5 g of DI water, 30 g of benzyl alcohol and 60 g of ethyl acetate, and mix on stir plate until dissolved.
- a ratio of aqueous phase to oil phase is 5:1.
- the organic phase is poured into the aqueous solution and homogenized using IKA for 10 seconds at room temperature to form course emulsion.
- the solution is fed through the homogenizer (110S) at 9 Kpsi (45 psi on gauge) for 2 discreet passes to form nanoemulsion.
- the emulsion is poured into quench (D.I. water) at ⁇ 5° C. while stirring on stir plate. Ratio of quench to emulsion is 8:1. 35% (w/w) Tween 80 is added in water to quench at ratio of 25:1 Tween 80 to drug.
- the nanoparticles are concentrated through TFF and the quench is concentrated on TFF with 500 kDa Pall cassette (2 membrane) to ⁇ 100 mL. Diafiltering is used using ⁇ 20 diavolumes (2 liters) of cold DI water, and the volume is brought down to minimal volume then collect final slurry, ⁇ 100 mL.
- the solids concentration of unfiltered final slurry is determined by the using tared 20 mL scintillation vial and adding 4 mL final slurry and dry under vacuum on lyo/oven and the weight of nanoparticles in the 4 mL of slurry dried down is determined.
- Concentrated sucrose (0.666 g/g) is added to final slurry sample to attain 10% sucrose.
- Solids concentration of 0.45 um filtered final slurry was determined by filtering about 5 mL of final slurry sample before addition of sucrose through 0.45 ⁇ m syringe filter; to tared 20 mL scintillation vial add 4 mL of filtered sample and dry under vacuum on lyo/oven.
- the remaining sample of unfiltered final slurry was frozen with sucrose.
- Composition Components by Wt.(%) mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/Vincristine 95/5 mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 46/46/8 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 47/47/6
- Drug was dissolved in the inner aqueous phase consisting of water with 1-arginine or NaOH used for solubilizing the drug.
- the polymer (16-5 PLA-PEG) was dissolved in the oil phase organic solvent system, such as dichloromethane (DCM) at 20% solid concentration.
- the outer aqueous phase consisted mainly of water with 1% sodium cholate (SC) as surfactant, unless noted otherwise.
- the w/o emulsion was prepared by adding the inner aqueous phase into the oil phase under rotor stator homogenization or sonication (using Branson Digital Sonifier) at a w/o ratio of 1:10.
- the coarse w/o/w emulsion was also prepared by adding the w/o emulsion into an outer aqueous phase under either rotor stator homogenization or sonication at o/w ratio of 1:10.
- the fine w/o/w emulsion was then prepared by processing the coarse emulsion through a Microfluidics high pressure homogenizer (M110S pneumatic) at 45000 psi with a 100 ⁇ m Z-interaction chamber.
- M110S pneumatic Microfluidics high pressure homogenizer
- the fine emulsion was then quenched into cold DI water at 10:1 quench:emulsion ratio.
- Polysorbate 80 (Tween 80) was then added as a process solubilizer to solubilize the unencapsulated drug. No drug precipitation was observed at a drug:Tween 80 ratio of 1:200.
- the batch was then processed with ultrafiltration followed by diafiltration to remove solvents, unencapsulated drug and solubilizer. The particle size measurements were performed by Brookhaven DLS and/or Horiba laser diffraction. To determine drug load, slurry samples were analyzed by HPLC and solid concentration analysis. The slurry retains were then diluted with sucrose to 10% before freezing. All ratios listed are on a w/w basis, unless specified otherwise.
- both the inner w/o and outer w/o/w emulsions were formed by rotor stator homogenization followed by 2 passes at 45 k psi using a high pressure homogenizer.
- the nanoparticle suspension was quenched in cold DI water followed by ultrafiltration/diafiltration work-up. HPLC and PSD analysis was used to determine that the drug load stayed at 0.38% for 131 nm particles.
- the emulsion process for all three batches remained similar. The highest drug load was obtained for the 16/5 PLA-PEG batch at 2.23% while the drug load was 0.2% and 0.04% for other batches.
- An organic phase is formed composed of a mixture of sirolimus and polymer (homopolymer, co-polymer, and co-polymer with ligand).
- the organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent.
- aqueous phase is composed of a surfactant and some dissolved solvent.
- the primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer.
- the primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer. The process is continued as in Example 12.
- Rapamycin (sirolimus) formulations are representative Rapamycin (sirolimus) formulations:
Abstract
Description
- This application claims priority to provisional applications U.S. Ser. No. 61/122,479, filed Dec. 15, 2008, U.S. Ser. No. 61/260,200, filed Nov. 11, 2009, and U.S. Ser. No. 61/249,022, filed Oct. 6, 2009, each of which is hereby incorporated by reference in its entirety.
- Nanoparticles for the delivery of therapeutic agents have the potential to circumvent many challenges associated with traditional delivery approaches including lack of patient compliance to prescribed therapy, adverse effects, and inferior clinical efficacy due to lack of targeted delivery. Important technological advantages of nanoparticles for drug delivery include the ability to deliver water-insoluble and unstable drugs, incorporation of both hydrophobic and hydrophilic therapeutic agents, and ability to utilize various routes of administration. Nanoparticle delivery systems may also facilitate targeted drug delivery and controlled release applications, enhance drug bioavailability at the site of action, reduce dosing frequency, and minimize side effects.
- Because of these possible advantages, nanoparticulate systems have been examined for use as drug delivery vehicles, including polymeric micelles, polymers, liposomes, low-density lipoproteins, dendrimers, hydrophilic drug-polymer complexes, and ceramic nanoparticles. Typical polymeric materials utilized in polymeric particulate drug delivery systems include polylactic acid (PLA), poly(D,L-glycolide) (PLG), and poly(lactide-co-glycolide) (PLGA). PLA and PLGA are listed as Generally Recognized as Safe (GRAS) under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are approved for use in commercially available microparticulate systems, including Decapeptyl®, Parlodel LA®, and Enantone Depot®, as well as in implant devices, such as Zoladex®.
- However, certain nanoparticle systems, such as liposomes, are not amenable for use with certain therapeutic agents. Polymeric nanoparticles developed to date have limited effectiveness, in part because such nanoparticles clear from the body quickly once administered and/or may accumulate in healthy tissue where treatment is not needed. Control of delivery of an active agent, using nanosystems, remains a challenge.
- Therefore there is a need for biocompatible compositions capable of extended delivery of active agents, e.g., anti-neoplastic agents, that provide for prolonged and/or increased plasma drug concentrations in a patient, especially as compared to administration of an active agent alone.
- In one aspect of the invention, a nanoparticle composition is provided that includes a biodegradable and/or biocompatible polymer and a therapeutic agent, wherein the biodegradable and/or biocompatible polymer matrix releases the therapeutic agent at a rate allowing controlled release of the agent over at least about 12 hours, or in some embodiments, at least about 24 hours For example, provided herein is a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a biocompatible polymer and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 12 hours when the composition is administered to a patient, and an area under the plasma concentration time curve (AUC) that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient.
- In an embodiment, disclosed herein is a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, said composition providing an elevated plasma concentration of the therapeutic agent for at least 6 hours, at least 12 hours, or at least 24 hours or more when the composition is administered to a patient, to provide an area under the plasma concentration time curve (AUC) that is increased by at least 100%, or at least by 150%, over the AUC provided when the therapeutic agent is administered alone to a patient.
- In some embodiments, disclosed nanoparticles may provide an actual peak plasma concentration (Cmax) that is at least 10% higher, or even at least 100% higher, as compared to a Cmax of said therapeutic agent when administered alone. Disclosed nanoparticles, for example, may provide a volume of distribution when administered to the patient that is less than or equal to about 5 plasma volumes. For example, disclosed nanoparticles and/or compositions may decrease the volume of distribution (Vz) by at least 50% as compared to the Vz of the patient when the therapeutic agent is administered alone.
- Disclosed biocompatible nanoparticle compositions may include long circulating nanoparticles that may further comprise a biocompatible polymer coupled to a targeting moiety, for example, a targeting moiety that is selected from the group consisting of a protein, peptide, antibody, antibody fragment, saccharide, carbohydrate, small molecule, glycan, cytokine, chemokine, nucleotide, lectin, lipid, receptor, steroid, neurotransmitter, cell surface marker, cancer antigen, or glycoprotein antigen. An exemplary targeting moiety may bind to prostate membrane specific antigen (PMSA). For example, a disclosed nanoparticle may include a biocompatible polymer coupled to a targeting moiety, e.g., a nanoparticle may include PLA-PEG-((S,S-2-{3-[1-carboxy-5-amino-pentyl]-ureido}-pentanedioic acid. Disclosed long circulating nanoparticles may include 1 to about 4% by weight, or 2% to about 4% by weight, of a biocompatible polymer coupled to a targeting moiety
- In some embodiments, a biocompatible nanoparticle may include a biocompatible polymer such as PLA-PEG. For example, a α-hydroxy polyester-co-polyether may be polylactic acid-co-polyethylene glycol, and/or a α-hydroxy polyester-co-polyether comprises about 16 kDa polylactic acid and about 5 kDa polyethylene glycol.
- Disclosed long circulating nanoparticles may be about 80 to about 90 weight percent α-hydroxy polyester-co-polyether.
- In some embodiments, disclosed long circulating nanoparticles may further comprise a biodegradable polymer, such as poly(lactic) acid. For example, long circulating nanoparticles may have about 40 to about 50 weight percent poly(lactic)acid, and about 40 to about 50 weight percent of α-hydroxy polyester-co-polyether. Compositions that include such biocompatible nanoparticles and a therapeutic agent may provide a peak plasma concentration (Cmax) of a therapeutic agent at least 100% higher than the Cmax of the therapeutic agent when administered alone, and/or the area under the plasma concentration time curve (AUC) may increased by at least 200% over the AUC of the therapeutic agent when administered alone to the patient.
- Disclosed nanoparticle compositions may include a therapeutic agent such as one selected from the group consisting of chemotherapeutic agents, diagnostic agents, prophylactic agents, nutraceutical agents, nucleic acids, proteins, peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and combinations thereof, for example, a nanoparticle may include an anti-neoplastic agent such as docetaxel, vincristine, methotrexate, paclitaxel, or sirolimus. Disclosed nanoparticle compositions may further include an aqueous solution of a saccharide.
- Also provided herein is a method of treating a solid tumor cancer, comprising administering disclosed nanoparticle composition to a patient (e.g. a mammal or primate) in need thereof. Such methods, may provide wherein at least 24 hours after administration, a solid tumor has significant concentration of therapeutic agent. Contemplated herein is a method of treating a solid tumor in a mammal in need thereof, comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, a single dose of said composition may provide extended elevated plasma concentrations of said therapeutic agent in the patient for a least one day, (e.g. the peak plasma concentration (Cmax) of the therapeutic agent after administration of the composition to the mammal is at least 10% higher than the Cmax of said therapeutic agent if administered in a non-nanoparticle formulation.)
- Also provided herein is a method of minimizing unwanted side effects or toxicity of an active agent in a patient, comprising: administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, wherein said composition is capable of delivery a higher plasma concentration of therapeutic agent to the patient as compared to administering the therapeutic agent alone, and wherein upon administering the nanoparticle composition the volume distribution of the active agent in the patient is reduced, as compared to the volume distribution if the therapeutic agent was administered alone. A method for modulating the plasma concentration of a therapeutic agent in a patient, e.g. a primate (e.g. human) is also provided, comprising: providing a polymeric nanoparticle comprising the therapeutic agent and administering the polymeric nanoparticle to the patient, thereby modulating the plasma concentration of the human patient.
- The invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings.
-
FIG. 1 is a schematic illustration of a nanoparticle according to one aspect of the present invention. -
FIG. 2 is a block diagram of the emulsion process used in the fabrication of nanoparticles in one aspect of the present invention. -
FIG. 3 depicts the in vitro release of docetaxel from nanoparticles and conventional docetaxel. -
FIG. 4 depicts the pharmacokinetics of docetaxel encapsulated in nanoparticles and conventional docetaxel in rats. -
FIG. 5 depicts the distribution of radioactivity determined in selected tissues of rats after IV administration of nanoparticles containing 14C-targeting polymer (▴), nanoparticles containing 14C-docetaxel (▪), and conventional 14C -docetaxel (♦). -
FIG. 6 depicts docetaxel concentration in tumor tissue after administration of docetaxel encapsulated in nanoparticles or conventional docetaxel to LNCaP tumor bearing SCID mice. -
FIG. 7 depicts the reduction in tumor volume in mice with PSMA-expressing LNCaP xenografts when treated with docetaxel encapsulated in nanoparticles or conventional docetaxel. -
FIG. 8 depicts pharmacokinetics of vincristine encapsulated in disclosed nanoparticles and conventional vincristine in rats. -
FIG. 9 depicts pharmacokinetics of methotrexate encapsulated in disclosed nanoparticles and conventional methotrexate in rats. -
FIG. 10 depicts pharmacokinetics of paclitaxel encapsulated in disclosed nanoparticles and conventional paclitaxel in rats. -
FIG. 11 depicts pharmacokinetics of rapamycin (sirolimus) encapsulated in disclosed nanoparticles and conventional rapamycin in rats. -
FIG. 12 depicts the tumor accumulation of docetaxel in disclosed nanoparticles in a MX-1 mouse breast tumor model. -
FIG. 13 depicts pharmacokinetics of docetaxel in a NHP model using various disclosed nanoparticles. - It is to be understood that the invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing particular versions or embodiments only and is not intended to limit the scope of the invention. All of the publications and references mentioned herein are incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
- As used herein the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Further, unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
- As used herein, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 40%-60%.
- An “effective amount” or “therapeutically effective amount” of a composition, as used herein, is a predetermined amount calculated to achieve a desired effect.
- As used herein, the term “long-circulating” refers to enhanced stability in the circulatory system of a patient, regardless of biological activity.
- As used herein, the prefix “nano” and the terms “nanophase” and “nanosize” refer to a special state of subdivision implying that a particle has an average dimension smaller than about 1000 nm (1000×10−9 m).
- As used herein, the terms “poly(ethylene glycol)” or “PEG” and “poly(ethylene oxide)” or “PEO” denote polyethers comprising repeat —CH2—CH2—O— units. PEG and/or PEO can be different polymers depending upon end groups and molecular weights. As used herein, poly(ethylene glycol) and PEG describes either type of polymer.
- An “α-hydroxy polyester” refers to polymers having monomers based on one or more α-hydroxy acid, such as poly(lactic) acid, poly(glycolic) acid, poly-lactic-co-glycolic acid, polycaprolactone.
- The term “target”, as used herein, refers to the cell type or tissue to which enhanced delivery of the therapeutic agent is desired. For example, diseased tissue may be a target for therapy.
- As used herein, the term “therapeutic agent” means a compound utilized to image, impact, treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
- In an embodiment, disclosed long-circulating nanoparticles include a therapeutic agent and biodegradable and/or biocompatible polymeric particles, optionally functionalized with targeting moieties. The nanoparticles are designed to circulate in a vascular compartment of a patient for an extended period of time, distribute and accumulate at a target, and release the encapsulated therapeutic agent in a controlled manner. These characteristics can result in an increased level of therapeutic agent in the target and a potential reduction in off-target exposure. For example, the disclosed nanoparticles remain in circulation longer because, upon administration to a patient (e.g. a mammal, primate (e.g. human)), the disclosed nanoparticles are substantially confined to the vascular compartment of the patient, and are engineered to be cleared very slowly.
- The activity of many therapeutic agents is dependent on their pharmacokinetic behavior. This pharmacokinetic behavior defines the drug concentrations and period of time over which cells are exposed to the drug. For most therapeutics, e.g. anti-neoplastics, longer exposure times are preferred as this results in increased killing of the cancer cells. In general, several parameters are used to describe drug pharmacokinetics. Peak plasma concentration, or maximum plasma concentration (Cmax) and area under the curve (AUC) are examples. AUC is a measure of plasma drug levels over time and provides an indication of the total drug exposure. Generally, plasma concentration and plasma AUC for a therapeutic agent correlate with increased therapeutic efficacy.
- The combination of long circulation time, confinement of particles to the vascular compartment and controlled release of drug results in higher circulating drug concentrations for longer periods of time (as evidenced by higher AUC and lower Vd).than drug alone, or, for example, drug in a PLA polymeric nanoparticles that does not include PLA-PEG, or that do not include e.g. PLA alone.
- For example, provided herein, in an embodiment, is a biocompatible nanoparticle composition comprising a plurality of long circulating nanoparticles, each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent. Such compositions may provide a therapeutic effect for at least 12 hours, at least 24 hours, or at least 36 hours, or 48 hours or more, upon administration to a patient. In some embodiments, peak plasma concentration (Cmax) of the therapeutic agent of such nanoparticles, e.g. when the composition is administered to a patient, may be least 10% higher, 20% higher, or about 10% to about 100% higher, or more, than the Cmax of the same therapeutic agent when administered alone. Actual peak plasma concentration of delivered therapeutic agent includes both agent that is released from the nanoparticle (e.g. after administration) and therapeutic agent remaining in any nanoparticle remaining in the plasma, e.g. at a given time.
- In another embodiment, disclosed nanoparticles may provide upon administration to a patient, an area under the plasma concentration time curve (AUC), that may be increased by at least 100%, at least 200%, or about 100% to about 500% or more, over the AUC of the therapeutic agent when administered alone to the patient. In another embodiment, a provided composition that includes disclosed nanoparticles may decrease the volume of distribution (Vz) of distributed active agent, upon administration, in a patient by at least 10%, or by at least 20%, or about 10% to about 100%, as compared to the Vz of the patient when the therapeutic agent is administered alone. For example, a provided nanoparticle composition may provide Vz in a patient that is on the same order of magnitude that the of plasma volume and/or a volume of distribution less than about 10 plasma volumes. For example, a disclosed nanoparticle composition may provide a Vz that is less than, or about, 2 times the plasma volume, or less than or about 8 plasma volumes. In an embodiment, a disclosed nanoparticle composition may provide a Vz in a patient that is on about the same order of plasma volume, (e.g. about 5 L for an exemplary 70 kg patient), e.g. about a Vz that indicates administered nanoparticles are substantially in the patient's plasma and not substantially in other tissues.
- In some embodiments, disclosed nanoparticles may be used as a drug delivery vehicle based on the encapsulation of a therapeutic agent in a polymer matrix with controlled porosity and/or a soluble shell or matrix that upon dissolution releases the therapeutic agent in the immediate vicinity of the targeted area. The protection of the therapeutic agent provided by the polymer shell or matrix allows for the delivery of therapeutic agents that are water-insoluble or unstable. Furthermore, dissolution kinetics of the polymer can be designed to provide sustained release of therapeutic agents at a target for an extended period of time.
- Disclosed nanoparticles can be used for a variety of applications, such as, without limitation, drug delivery, gene therapy, medical diagnosis, and for medical therapeutics for cancer, pathogen-borne diseases, hormone-related diseases, reaction-by-products associated with organ transplants, and other abnormal cell or tissue growth.
- Provided herein, in an embodiment, are methods for treating a patient e.g. a mammal suffering from cancer, e.g. a solid tumor cancer, prostate cancer, breast cancer or lung cancer using e.g., disclosed nanoparticles. However, contemplated diseases that may be treated using disclosed nanoparticles include a broad range of diseases and find limitation only by e.g. the therapeutic agent, the availability of a marker and/or a targeting ligand for the disease.
- In other embodiments, a nanoparticle delivery system is provided that mitigates against colloidal instability, agglomeration, polydispersity in nanoparticle size and shape, swelling, and leakage of encapsulated materials.
- In yet another embodiment, nanoparticles for delivery of therapeutic agents are provided that exhibit encapsulation efficiency. Encapsulation efficiency is affected by factors including, for example, material characteristics of the polymer utilized as the carrier matrix, the chemical and physical properties of the therapeutic agent to be encapsulated, and type of solvents used in the nanoparticle fabrication process.
- In yet another aspect, polymeric nanoparticles for delivery of therapeutic agents are provided that exhibit particle heterogeneity. Conventional polymeric nanoparticle fabrication techniques generally provide multimodal particle size distributions as a result of self-aggregation during nanoprecipitation of both the polymer and the drug molecules.
- Polymeric nanoparticles for delivery of therapeutic agents are provided, in an embodiment, that may reduce or eliminate burst release effects. Conventional polymeric nanoparticle carriers frequently exhibit a bimodal drug release pattern with up to about 40-80% or more of the encapsulated drug released during the first several hours. After 24 to 48 hours, drug release is significantly reduced due to the increased diffusion barrier for drug molecules located deep within the polymer matrix. In such conventional nanoparticle carrier systems, poorly encapsulated drug molecules diffuse quickly into solution, which may lead to significant toxicity in vivo. Further, by the time the evacuated nanoparticles arrive and accumulate at the targeted site (e.g., tumor tissue), the nanoparticles generally have little or no remaining therapeutic efficacy.
- In an embodiment, polymeric nanoparticles for delivery of therapeutic agents are provided that may evade rapid capture by the reticuloendothelial system (RES), leading to extended circulation time and elevated concentration of the nanoparticles in the blood. Rapid capture and elimination is typically caused by the process of opsonization in which opsonin proteins present in the blood serum quickly bind to conventional nanoparticles, allowing macrophages to easily recognize and remove these particulates before they can perform their designed therapeutic function. The extent and nature of opsonin adsorption at the surface of nanoparticles and their simultaneous blood clearance depend on the physicochemical properties of the particles, such as size, surface charge, and surface hydrophobicity. In yet another embodiment, a nanoparticle composition is provided including a biodegradable and/or biocompatible polymer matrix and a therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix wherein the clearance rate of said therapeutic agent coupled to the biodegradable and/or biocompatible polymer matrix is lower than the clearance rate of said therapeutic agent when administered alone.
- In certain embodiments, methods are provided that mask or camouflage nanoparticles in order to evade uptake by the RES. One such method is the engineering of particles in which polyethers, such as poly(ethylene glycol) (PEG) or PEG containing surfactants, are deployed on the surface of nanoparticles. The presence of PEG and/or PEG-containing copolymers, e.g. on the surface of nanoparticles can result in an increase in the blood circulation half-life of the nanoparticles by several orders of magnitude. This method creates a hydrophilic protective layer around the nanoparticles that is able to repel the absorption of opsonin proteins via steric repulsion forces, thereby blocking and delaying the first step in the opsonization process.
-
FIG. 1 schematically illustrates a nanoparticle according to one aspect of the present invention. As shown inFIG. 1 ,docetaxel 100, an anti-neoplastic agent approved for the treatment of hormone refractory prostate cancer (HRPC), is encapsulated in a matrix 110 derived from the biodegradable and/or biocompatible polymers PLA and poly(lactide-b-ethylene glycol) (PLA-PEG). The polymer matrix 110 contains a targeting polymer (PLA-PEG-lys(urea)glu) 120 that is end-functionalized (through the 5 amino moiety) with the lysine-urea-glutamate heterodimer (S,S-2-{3-[1-carboxy-5-amino-pentyl]-ureido}-pentanedioic acid (lys(urea)glu) 130, a small molecule ligand that selectively binds to PSMA, a clinically relevant prostate cancer cell surface marker. - Once the nanoparticles, e.g. as provided herein are administered, at least portions of the nanoparticle polymer(s) may be biologically degraded by, for example, enzymatic activity or cellular machinery into monomers and/or other moieties that cells can either use or excrete. In certain aspects of the invention, the dissolution or degradation rate of the nanoparticles is influenced by the composition of the polymer shell or matrix. For example, in some embodiments, the half-life of the polymer (the time at which 50% of the polymer is degraded into monomers and/or other nonpolymeric moieties) may be on the order of days, weeks, months, or years, depending on the polymer.
- According to some aspects of the invention, nanoparticle delivery characteristics such as water uptake, controlled release of therapeutic agent, and polymer degradation kinetics may be optimized through selection of polymer shell or matrix composition.
- Suitable polymers that may form some of the disclosed nanoparticles may include, but are not limited to, biodegradable α-hydroxy polyesters and biocompatible polyethers. In some aspects, exemplary polyesters include, for example, PLA, PLGA, PEG, PEO, PEGylated polymers and copolymers of lactide and glycolide (e.g., PEGylated PLA, PEGylated PGA, PEGylated PLGA), and derivatives thereof. In other aspects, suitable polymers include, for example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene inline), PEGylated poly(ethylene imine), poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[a-(4-aminobutyl)-L-glycolic acid], and combinations and derivatives thereof.
- In other aspects, a polymer matrix may comprise one or more acrylic polymers. Exemplary acrylic polymers include, for example, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid polyacrylamide) copolymer, aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, polycyanoacrylates, and combinations thereof. The matrix may include dextran, acylated dextran, chitosan (e.g., acetylated to various levels), poly(vinyl) alcohol (for example, hydrolyzed to various degrees), and/or alginate, e.g. alginate complexed to bivalent cations such as a calcium alginate complex.
- Nanoparticles disclosed herein include one, two, three or more biocompatible and/or biodegradable polymers. For example, a contemplated nanoparticle may include about 10 to about 99 weight percent of one or more block co-polymers that include a biodegradable polymer and polyethylene glycol, and about 0 to about 50 weight percent of a biodegradable homopolymer. Exemplary therapeutic nanoparticles may include about 40 to about 90 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer or about 40 to about 80 weight percent poly(lactic) acid-poly(ethylene)glycol copolymer. Such poly(lactic) acid-block-poly(ethylene)glycol copolymer may include poly(lactic acid) having a number average molecular weight of about 15 to 20 kDa (or for example about 15 to about 100 kDa, e.g., about 15 to about 80 kDa), and poly(ethylene)glycol having a number average molecular weight of about 2 to about 10 kDa, for example, about 4 to about 6 kDa. For example, a disclosed therapeutic nanoparticle may include about 70 to about 90 weight percent PLA-PEG and about 5 to about 25 weight percent active agent (e.g. docetaxel), or about 30 to about 50 weight percent PLA-PEG, about 30 to about 50 weight percent PLA or PLGA, and about 5 to about 25 weight percent active agent (e.g. doxetaxel). Such PLA ((poly)lactic acid) may have a number average molecular weight of about 5 to about 10 kDa. Such PLGA (poly lactic-co-glycolic acid) may have a number average molecular weight of about 8 to about 12 kDa. It should be appreciated that disclosed PLA-PEG copolymers may include a chemical linker, oligomer, or polymer chain between the PLA and PEG blocks, e.g., may include PLA-linker-PEG.
- For example, disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. about 10 weight percent docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa, e.g. about 87.5% PLA-PEG (16 kDa/5 kDa)), and optionally e.g. a PLA-PEG-lys(urea)-glu (e.g. at 2.5 weight percent).
- Alternatively, a disclosed nanoparticle, which may have slow release properties, may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), (e.g. 43.25% PLA-PEG), about 42 to 45 weight percent PLA (e.g. about 75 kDa) (e.g. 43.25% PLA/75 kDa) and about 10 to 15 weight percent active agent (e.g. docetaxel). For example, disclosed nanoparticles may optionally include about 1 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid (which does not include PEG, e.g a homopolymer of PLA), or may optionally include about 1 to about 50 weight percent, or about 10 to about 50 weight percent or about 30 to about 50 weight percent poly(lactic) acid or poly(lactic) acid-co-poly (glycolic) acid. In an embodiment, disclosed nanoparticles may include two polymers, e.g. PLA-PEG and PLA, in a weight ratio of about 30:60 to about 60:30, e.g, about 40:60, about 60:40, or about 50:50.
- Such substantially homopolymeric poly(lactic) or poly(lactic)-co-poly(glycolic) acid may have a weight average molecular weight of about 10 to about 130 kDa, for example, about 20 to about 30 kDa, or about 100 to about 130 kDa. Such homopolymeric PLA may have a number average molecule weight of about 5 to about 90 kDa, or about 5 to about 12 kDa, about 15 to about 30 kDa, or about 60 to about 90 kDa. Exemplary homopolymeric PLA may have a number average molecular weight of about 80 kDa or a weight average molecular weight of about 124 kDa. As is known in the art, molecular weight of polymers can be related to an inherent viscosity. In some embodiments, homopolymer PLA may have an inherent viscosity of about 0.2 to about 0.4, e.g. about 0.3; in other embodiments, PLA may have an inherent viscosity of about 0.6 to about 0.8. Exemplary PLGA may have a number average molecular weight of about 8 to about 12 kDa.
- In other embodiments, modified surface chemistry and/or small particle size of disclosed nanoparticles may contribute to the effectiveness of the nanoparticles in the delivery of a therapeutic agent. For example, in one disclosed aspect, nanoparticle surface charge may be modified to achieve slow biodegradation and reduce clearance of the nanoparticles. In another aspect, porosity of the polymer shell or matrix is optimized to achieve extended and controlled release of the therapeutic agent. For example, in one embodiment of the invention, the nanoparticles may have porosity in the range of about 10 to about 90 percent and/or a pore diameters in the range of about 0.001 to about 0.01 microns. Further, without wishing to be bound by theory, because of their small size and persistence in the circulation, the nanoparticles according to some embodiments of the invention may be able to penetrate the altered and often compromised vasculature of tumors via the enhanced permeability and retention (EPR) effect resulting in preferential accumulation of nanoparticles in tumor interstitium.
- Examples of therapeutic agents that may form part of the disclosed nanoparticles include, but are not limited to, chemotherapeutic agents (e.g. anti-cancer agents), diagnostic agents (e.g. contrast agents, radionuclides, and fluorescent, luminescent, and magnetic moieties), prophylactic agents (e.g. vaccines), nutraceutical agents (e.g. vitamins and minerals), nucleic acids (e.g., siRNA, RNAi, and mircoRNA agents), proteins (e.g. antibodies), peptides, lipids, carbohydrates, hormones, small molecules, metals, ceramics, drugs, vaccines, immunological agents, and/or combinations thereof. For example, the active agent or drug may be a therapeutic agent such as an antineoplastic such as a mTor inhibitor (e.g., sirolimus (rapamycin), temsirolimus, or everolimus), vinca alkaloids such as vincristine, a diterpene derivative, a taxane such as paclitaxel (or its derivatives such as DHA-paclitaxel or PG-paxlitaxel), docetaxel, or methatrexate.
- In some aspects of the invention, the therapeutic agent to be delivered is an agent useful in the treatment of cancer (e.g., a solid tumor cancer e.g., prostate or breast cancer). Such therapeutic agents may include, for example, doxorubicin (adriamycin), gemcitabine (gemzar), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere), mitoxantrone, mitoxantrone hydrochloride, aldesleukin, asparaginase, busulfan, carboplatin, cladribine, camptothecin, CPT-I1, 1O-hydroxy-7-ethylcamptothecin (SN38), dacarbazine, S-I capecitabine, ftorafur, 5′deoxyflurouridine, UFT, eniluracil, deoxycytidine, 5-azacytosine, 5-azadeoxycytosine, allopurinol, 2-chloroadenosine, trimetrexate, aminopterin, methylene-10-deazaaminopterin (MDAM), oxaplatin, picoplatin, tetraplatin, satraplatin, platinum-DACH, ormaplatin, CI-973, JM-216, and analogs thereof, epirubicin, etoposide phosphate, 9- aminocamptothecin, 10,11-methylenedioxycamptothecin, karenitecin, 9-nitrocamptothecin, TAS 103, vindesine, L-phenylalanine mustard, ifosphamidemefosphamide, perfosfamide, trophosphamide carmustine, semustine, epothilones A-E, tomudex, 6-mercaptopurine, 6-thioguanine, amsacrine, etoposide phosphate, karenitecin, acyclovir, valacyclovir, ganciclovir, amantadine, rimantadine, lamivudine, zidovudine, bevacizumab, trastuzumab, rituximab and combinations thereof.
- In some embodiments, contemplated nanoparticles may include more than one therapeutic agent. Such nanoparticles may be useful, for example, in aspects where it is desirable to monitor a targeting moiety as such moiety directs a nanoparticle containing a drug to a particular target in a subject.
- Disclosed nanoparticles may be formed using an emulsion process, e.g. as presented as a block diagram in
FIG. 2 . As shown inFIG. 2 , an organic polymer/drug solution containing docetaxel, PLA, PLA-PEG, and PLA-PEG-lys(urea)glu dissolved in a co-solvent mixture of ethyl acetate and benzyl alcohol is dispersed in an aqueous solution of sodium cholate, ethyl acetate, and benzyl alcohol to form a coarse emulsion. In some aspects the conditions under which the emulsion process is performed favor the orientation of the PEG and/or PEG-lys(urea)glu polymer chains toward the particle surface. In other aspects, an orientation is achieved where the PEG is folded within the nanoparticle polymer shell or matrix. - As presented in
FIG. 2 , a coarse emulsion can be passed through a high pressure homogenizer to reduce the droplet size, forming a fine emulsion. The fine emulsion is diluted into an excess volume of a quench solution of coldwater containing polysorbate 80. The presence ofpolysorbate 80 serves to remove excess therapeutic agent that has not been encapsulated in the nanoparticle. In some aspects of the present invention,polysorbate 80 may also be adhered or associated with a nanoparticle surfaces. While not wishing to be bound by theory,polysorbate 80 coupled to the nanoparticle surfaces may impact characteristics such as controlled release of therapeutic agent and polymer degradation kinetics. Quenching may be performed at least partially at a temperature of about 5° C. or less. For example, water used in the quenching may be at a temperature that is less that room temperature (e.g., about 0 to about 10° C., or about 0 to about 5° C.). - In some embodiments, not all of the therapeutic agent (e.g., docetaxel) is encapsulated in the particles at this stage, and a drug solubilizer is added to the quenched phase to form a solubilized phase. The drug solubilizer may be for example,
Tween 80,Tween 20, polyvinyl pyrrolidone, cyclodextran, sodium dodecyl sulfate, or sodium cholate. For example, Tween-80 may added to the quenched nanoparticle suspension to solubilize the free drug and prevent the formation of drug crystals. In some embodiments, a ratio of drug solubilizer to therapeutic agent (e.g., docetaxel) is about 100:1 to about 10:1. - Ethyl acetate and benzyl alcohol are extracted from the organic phase droplets, resulting in formation of a hardened nanoparticle suspension. For example, docetaxel or other active agent may be encapsulated at e.g. a loading level of 10% w/w; corresponding to more than 10,000 drug molecules per nanoparticle.
- The nanoparticle suspension is processed using tangential flow ultrafiltration/diafiltration (UF/DF) with cold water to remove processing aids and to concentrate the nanoparticles to a desired value. Residual precursor materials and excess organics present in unwashed nanoparticle suspensions may have a detrimental impact on biomedical applications as well as undesired toxic effects on the physiological system. The washed nanoparticle suspension is then passed through a prefilter and at least two sterilizing-grade filters.
- Once the nanoparticles have been prepared, they may be combined with an acceptable carrier to produce a pharmaceutical formulation, according to another aspect of the invention. As would be appreciated by one of skill in this art, the carrier may be selected based on factors including, but not limited to, the route of administration, the location of the targeted disease tissue, the therapeutic agent being delivered, and/or the time course of delivery of the therapeutic agent. For example, as shown in
FIG. 2 , a concentrated sucrose solution is aseptically added to the sterile nanoparticle suspension to produce a pharmaceutical formulation. The sucrose serves as a cryoprotectant and a tonicity agent. In this embodiment, the resulting pharmaceutical formulation is a sterile, aqueous, injectable suspension of docetaxel encapsulated in nanoparticles comprised of biocompatible and biodegradable polymers. The suspension is assayed for docetaxel content, and may be aseptically diluted to the desired concentration. In some embodiments, the particle suspension is aseptically filled and sealed in glass vials. In other embodiments, the bulk drug product suspension is stored frozen at −20° C.±5° C. prior to filling into vials. - The fabrication methods for the nanoparticles of the invention may be modified in some embodiments to achieve desired drug-delivery features. For example, nanoparticle characteristics such as surface functionality, surface charge, particle size, zeta (ζ) potential, hydrophobicity, controlled release capability, and ability to control immunogenicity, and the like, may be optimized for the effective delivery of a variety of therapeutic agents. Furthermore, the long-circulating nanoparticles produced according to the emulsion process shown in
FIG. 2 are well dispersed and unagglomerated, which facilitates conjugation or functionalization of the nanoparticle surfaces with targeting moieties. - Disclosed nanoparticles may include optional targeting moieties, which may be selected to ensure that the nanoparticles selectively attach to, or otherwise associate with, a selected marker or target. For example, in some embodiments, disclosed nanoparticles may be functionalized with an amount of targeting moiety effective for the treatment of prostate cancer in a subject (e.g., a low-molecular weight PSMA ligand). Through functionalization of nanoparticle surfaces with such targeting moieties, the nanoparticles are effective only at targeted sites, which minimizes adverse side effects and improves efficacy. Targeted delivery also allows for the administration of a lower dose of therapeutic agent, which may reduce undesirable side effects commonly associated with traditional treatments of disease.
- In certain aspects, disclosed nanoparticles may be optimized with a specific density of targeting moieties on the nanoparticle surface, such that e.g., an effective amount of targeting moiety is associated with the nanoparticle for delivery of a therapeutic agent. For example, the fraction of the the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety may be less than 80% of the total. According to another embodiment, the fraction of the biodegradable and/or biocompatible polymer matrix functionalized with a targeting moiety is less than about 50% of the total. Increased density of the targeting moiety may, in some embodiments, increase target binding (cell binding/target uptake).
- Exemplary targeting moieties include, for example, proteins, peptides, antibodies, antibody fragments, saccharides, carbohydrates, glycans, cytokines, chemokines, nucleotides, lectins, lipids, receptors, steroids, neurotransmitters and combinations thereof. The choice of a marker may vary depending on the selected target, but in general, markers that may be useful in embodiments of the invention include, but are not limited to, cell surface markers, a cancer antigen (CA), a glycoprotein antigen, a melanoma associated antigen (MAA), a proteolytic enzyme, an angiogenesis marker, a prostate membrane specific antigen (PMSA), a small cell lung carcinoma antigen (SCLCA), a hormone receptor, a tumor suppressor gene antigen, a cell cycle regulator antigen, a proliferation marker, and a human carcinoma antigen. Exemplary targeting moieties include:
- -lys-(urea)glu, which may be conjugated to PEG, e.g. a disclosed nanoparticle may include PLA-PEG-targeting moiety, e.g. S,S-2-{3-[1-carboxy-5-amino-pentyl]-ureido}-pentanedioic acid. For example, disclosed nanoparticles may include about 10 to 15 weight percent active agent (e.g. docetaxel), and about 86 to about 90 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa), and about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16 kDa/5 kDa PLA-PEG). Alternatively, a disclosed nanoparticle may include about 42 to about 45 weight percent PLA-PEG (with e.g. PLA about 16 kDa and PEG about 5 kDa) about 42 to 45 weight percent PLA (e.g. about 75 kDa), about 10 to 15 weight percent active agent (e.g. docetaxel), and about about 2 to about 3 weight percent PLA-PEG-lys(urea)glu (16/5 PLA-PEG).
- In other aspects of the invention, targeting moieties are targeted to an antigen associated with a disease of a patient's immune system or a pathogen-borne condition. In yet another aspect, targeting moieties are targeted to cells present in normal healthy conditions. Such targeting moieties may be directly targeted to a molecule or other target or indirectly targeted to a molecule or other target associated with a biological molecular pathway related to a condition.
- The amount of nanoparticles administered to a patient may vary and may depend on the size, age, and health of the patient, the therapeutic agent to be delivered, the disease being treated, and the location of diseased tissue. Moreover, the dosage may vary depending on the mode of administration.
- Various routes of administration are contemplated herein. In a particular aspect, the nanoparticles are administered to a subject systemically. Further, in some aspects, methods of administration may include, but are not limited to, intravascular injection, intravenous injection, intraperitoneal injection, subcutaneous injection, and intramuscular injection. According to aspects of the present invention, the nanoparticles necessitate only a single or very few treatment sessions to provide effective treatment of disease, which ultimately may facilitate patient compliance. For example, in some aspects, administration of the nanoparticles can occur via intravenous infusion once every three weeks.
- Also contemplated herein are methods of treating solid tumors, e.g. prostate, lung, breast or other cancers, comprising administering a disclosed nanoparticle composition to a patient, e.g. a mammal in need thereof. For example, after such administration, e.g. at least after 12 hours, 24 hours, 36 hours, or 48 hours, or more after administration, the solid tumor may have significant concentration of therapeutic agent, e.g. may have an increase in tumor drug concentration of at least about 20%, or at least about 30% or more active agent (e.g. docetaxel) as compared to the amount present in a tumor after administration of (e.g. the same dosage) of therapeutic agent alone (e.g. not in a disclosed nanoparticle composition).
- Disclosed herein is a method of treating a solid tumor in a mammal comprising administering a nanoparticle composition comprising a plurality of nanoparticles each comprising a α-hydroxy polyester-co-polyether and a therapeutic agent, wherein the composition has an amount of therapeutic agent effective to inhibit the growth of said tumor, for example, wherein single dose of said composition provides extended release of said therapeutic agent for a least one day. Such methods may provide an actual peak plasma concentration (Cmax) of the therapeutic agent after administration of the composition to the mammal that is at least 10% higher, or at least 20% higher or 100% higher or more than the Cmax of said therapeutic agent if administered in a non-nanoparticle formulation. Disclosed methods may provide, upon administration of nanoparticles, an area under the plasma concentration time curve (AUC) in a patient that is increased by at least 100% over the AUC provided when the therapeutic agent is administered alone to a patient. In some embodiments, disclosed methods may also, alone or in addition to the above plasma parameters, decrease the volume of distribution (Vz) of the therapeutic agent upon administration by at least 50% as compared to the Vz of the patient when the therapeutic agent is administered alone.
- A method of minimizing unwanted side effects or toxicity of an active or therapeutic agent in a patient is also provided herein. For example, disclosed nanoparticles, may, upon administration, provide a higher plasma concentration of therapeutic agent as compared to administering an equivalent dosage of therapeutic agent alone. However, upon administration, in some embodiments, disclosed nanoparticles circulate substantially in the vascular compartment, and therefore may not contribute significantly to other areas that may cause toxicity or unwanted side effects.
- In order that the invention disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.
- A suspension of docetaxel encapsulated in nanoparticles fabricated according to the emulsion process depicted in
FIG. 2 and Example 12 using 87.5 weight percent PLA-PEG, 10 wt. % docetaxel, and 2.5 wt. percent docetaxel (Formulation A) (all docetaxel nanoparticle formulations used in these Examples were in a composition of 5% nanoparticles, 65% water, and 30% sucrose). was placed in a dialysis cassette and incubated in a reservoir of phosphate buffered saline (PBS) at 37° C. with stirring. Samples of the dialysate were collected and analyzed for docetaxel using reversed phase high performance liquid chromatography (HPLC). For comparison, conventional docetaxel was analyzed under the same procedure. -
FIG. 3 presents the in vitro release profile of docetaxel encapsulated in nanoparticles compared to conventional docetaxel. Release of the encapsulated docetaxel from the polymer matrix was essentially linear over the first 24 hours with the remainder gradually released over a period of about 96 hours. - Six- to eight-week old male Sprague-Dawley rats were administered a single bolus dose (5 mg/kg of docetaxel) of docetaxel encapsulated in nanoparticles or conventional docetaxel via a tail vein. The dose groups consisted of six rats each. Blood was drawn at 0.083, 0.5, 1, 2, 3, 4, 6, and 24 hours post-dosing and processed to plasma. The concentration of total docetaxel in plasma was measured by a liquid chromatography-mass spectrometry (LC-MS) method following extraction with methyl tert-butyl ether (MTBE). The MTBE extraction does not differentiate nanoparticle-encapsulated docetaxel from docetaxel that was released from the nanoparticles into the plasma, and as such, the LC-MS data does not distinguish between the two.
-
FIG. 4 and Example Table 2.1 present the observed pharmacokinetic profiles and pharmacokinetic parameters, respectively, of docetaxel encapsulated in nanoparticles and conventional docetaxel. Example Table 2.1 further includes data from the preclinical development of TAXOTERE® for comparative reference (Bissery et al. 1995). The results for conventional docetaxel were consistent with those reported in literature (Bissery et al. 1995), indicating docetaxel was rapidly cleared from the blood and distributed to tissues. The peak plasma concentration (Cmax) was observed at the first sampling time point for all treatments. - The Cmax and AUC of the docetaxel encapsulated in nanoparticles were approximately 100 times higher than that for conventional docetaxel. The difference in the Cmax may be attributable to having missed the rapid initial tissue distribution phase for conventional docetaxel. The data indicate that the docetaxel encapsulated in nanoparticles largely remains in circulation upon injection and is slowly cleared over a 24 hour period. The data further shows that docetaxel is released from the nanoparticles in a controlled manner during the 24 hour period (e.g., rapid burst release is not observed). If the nanoparticles were very quickly cleared from circulation, the large increase in AUC would not be observed. Similarly, if there was rapid burst release of docetaxel from the nanoparticles, the pharmacokinetic profile would be expected to more closely resemble that of conventional docetaxel.
-
EXAMPLE TABLE 2.1 Summary of Docetaxel Encapsulated in Nanoparticles and Conventional Docetaxel Pharmacokinetic Parameters Dose tmax a Cmax t1/2 AUC0-∞ CL Species (mg/kg) (min) (ng/mL) (h) (ng/mL · h) (L/h/kg) Conventional Sprague- 5 2 4,100 0.8b 910 5.5 Docetaxel Dawley Rats (Bissery et al. 1995) Conventional Sprague- 5 5 600 4.4c 623 2.33 Docetaxel Dawley Rats Docetaxel Sprague- 5 5 54,800 2.6c 57,300 0.01 Encapsulated in Dawley Rats Nanoparticles aFor each treatment, tmax equals the first sampling time. bThe study duration was 6 hours. cThe half life was determined from 2-12 hours. - Six- to eight-week old male Sprague-Dawley rats were administered a single bolus intravenous dose of one of the following: (1) docetaxel encapsulated in nanoparticles in which the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14C-labeled, (2) docetaxel encapsulated in nanoparticles in which the encapsulated docetaxel was 14C-labeled, (3) 14C-labeled conventional docetaxel.
- Blood was drawn at 1, 3, 6, 12, and 24 hours post-dosing and processed to plasma. Immediately following blood collection, the rats were euthanized by CO2 asphyxiation and tissues were immediately collected, blotted, weighed, and frozen on dry ice. Tissue samples were stored frozen (approximately −70° C.) until analysis for radioactivity by liquid scintillation (LS) counting.
- As shown in
FIG. 5 , the docetaxel encapsulated in nanoparticles was gradually cleared from the plasma, exhibiting an approximate 2-fold decrease in plasma concentration over the 24 hour period studied. These results are indicative of limited or delayed nanoparticle clearance via the mononuclear phagocyte system (MPS) relative to that often observed for particulate formulations. Without wishing to be bound by theory, this difference in plasma clearance times may be attributed to certain nanoparticle characteristics, including particle size and surface properties (e.g., surface charge and porosity). - The distinctions in plasma profiles of docetaxel encapsulated in nanoparticles and conventional docetaxel indicate that encapsulation of docetaxel in the nanoparticles prevents it from being rapidly distributed from the plasma compartment, resulting in significantly higher Cmax and AUC values relative to conventional docetaxel.
- The differences in the profiles of docetaxel encapsulated in nanoparticles wherein the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14C-labeled and the docetaxel encapsulated in nanoparticles wherein the encapsulated docetaxel was 14C-labeled are reflective of the controlled release of docetaxel from the polymeric matrix of the nanoparticles. If docetaxel was released very quickly from the nanoparticles, it would be expected to be rapidly distributed from the plasma, yielding a profile similar to that of conventional docetaxel. Conversely, if docetaxel was retained in the nanoparticles over this timeframe, the profiles of the docetaxel encapsulated in nanoparticles wherein the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14C-labeled and the docetaxel encapsulated in nanoparticles wherein the encapsulated docetaxel was 14C-labeled would be superimposable.
- Example Tables 3.1, 3.2, and 3.3 present the tissue distribution of radioactivity determined in rats after intravenous (IV) administration of (1) docetaxel encapsulated in nanoparticles in which the ligand of the PLA-PEG-lys(urea)glu targeting polymer was 14C-labeled, (2) docetaxel encapsulated in nanoparticles in which the encapsulated docetaxel was 14C-labeled, and (3) 14C-labeled conventional docetaxel, respectively. Example
FIG. 5 contains the radioactivity concentration curves of the test articles determined in plasma, liver, spleen, and bone marrow. - Lower levels of nanoparticles (i.e., radioactivity from the 14C-labeled targeting polymer) were detected in all tissues relative to plasma except in the spleen, where nanoparticle concentrations were higher than plasma at 12 and 24 hours. It cannot be determined to what extent the radioactivity in tissues reflect the content in blood contained within the tissues versus the tissues themselves, because the tissues were not exsanguinated.
- At time points closely following administration, the concentration of docetaxel encapsulated in nanoparticles was higher in most tissues than conventional docetaxel. After 24 hours, the concentration of docetaxel derived from the nanoparticles was lower than or approximately the same as the concentration of conventional docetaxel in all of the tissues evaluated, except the spleen.
- Although the concentration of docetaxel encapsulated in nanoparticles was higher than conventional docetaxel at early timepoints and throughout the 24 hour period in the spleen, the nanoparticles doped with docetaxel were well tolerated at approximately 10 mg/kg docetaxel dose. In addition, body weight changes and clinical observations in the Sprague-Dawley rats indicate that the docetaxel encapsulated in nanoparticles was tolerated as well as conventional docetaxel through a range of acute doses (5-30 mg/kg docetaxel).
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EXAMPLE TABLE 3.1 Tissue Distribution of Radioactivity Determined in Rats after IV Administration of Nanoparticles Containing 14C-Targeting Polymer. Bone Small Large Time Plasma Liver Spleen Heart Lungs Marrow Intestine Intestine (h) (nCi/mL) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) 1 2341 ± 168 337 ± 14 829 ± 26 180 ± 23 294 ± 78 109 ± 25 56 ± 2.5 36 ± 3.1 3 2023 ± 58 334 ± 43 1141 ± 75 190 ± 62 264 ± 38 191 ± 122 50 ± 5.4 33 ± 3.6 6 2001 ± 71 364 ± 23 1789 ± 173 174 ± 25 263 ± 40 372 ± 8.7 48 ± 8.0 43 ± 10 12 1445 ± 59 375 ± 41 2079 ± 205 151 ± 21 266 ± 24 390 ± 58 71 ± 3.6 40 ± 6.1 24 998 ± 55 398 ± 59 2808 ± 238 119 ± 11 218 ± 26 594 ± 248 88 ± 17 38 ± 5.0 -
EXAMPLE TABLE 3.2 Tissue Distribution of Radioactivity Determined in Rats after IV Administration of Nanoparticles Containing 14C-Docetaxel. Bone Small Large Time Plasma Liver Spleen Heart Lungs Marrow Intestine Intestine (h) (nCi/mL) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) 1 753 ± 149 267 ± 45 889 ± 43 156 ± 15 277 ± 27 142 ± 20 409 ± 158 71 ± 24 3 265 ± 52 127 ± 12 999 ± 94 80 ± 3.6 154 ± 9.0 127 ± 17 219 ± 30 151 ± 37 6 140 ± 38 88 ± 9.7 972 ± 44 69 ± 9.8 118 ± 23 121 ± 5.9 119 ± 20 133 ± 38 12 24 ± 1.9 47 ± 6.3 854 ± 56 41 ± 2.1 58 ± 8.4 89 ± 9.3 50 ± 2.7 98 ± 14 24 5.7 ± 1.0 22 ± 3.1 634 ± 95 23 ± 1.3 44 ± 2.5 33 ± 8.2 43 ± 9.3 58 ± 4.9 -
EXAMPLE TABLE 3.3 Tissue Distribution of Radioactivity Determined in Rats after IV Administration of Conventional 14C-Docetaxel. Bone Small Large Time Plasma Liver Spleen Heart Lungs Marrow Intestine Intestine (h) (nCi/mL) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) (nCi/g) 1 4.9 ± 0.4 78 ± 15 100 ± 9.4 71 ± 2.5 82 ± 9.6 97 ± 4.2 517 ± 99 54 ± 3.6 3 1.9 ± 0.2 49 ± 7.3 81 ± 7.5 39 ± 1.5 66 ± 0.7 83 ± 1.0 122 ± 43 166 ± 37 6 1.6 ± 0.5 49 ± 11 82 ± 4.6 33 ± 1.3 993 ± 1605* 78 ± 1.9 62 ± 5.2 185 ± 82 12 0.8 ± 0.2 55 ± 7.4 77 ± 11 28 ± 1.7 1438 ± 1218* 62 ± 9.4 41 ± 4.9 83 ± 18 24 0.6 ± 0.1 43 ± 4.0 85 ± 8.6 24 ± 2.6 962 ± 99* 41 ± 6.8 47 ± 19 48 ± 34 *Samples likely contaminated during collection/analysis - Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 300 mm3. At this time, a single intravenous (IV) dose of 50 mg/kg docetaxel was administered as either docetaxel encapsulated in nanoparticles or conventional docetaxel. The test subjects were sacrificed 2 hour or 12 hour post-dose. The tumors from each group were excised and assayed for docetaxel using liquid chromatography-mass spectrometry (LC-MS).
- The measured docetaxel concentrations in tumors excised from the test subjects dosed with docetaxel encapsulated in nanoparticles or conventional docetaxel are presented in Example Table 4.1 and
FIG. 6 . At 12 hours post-dose, the tumor docetaxel concentration in test subjects receiving docetaxel encapsulated in nanoparticles was approximately 7 times higher than in the test subjects receiving conventional docetaxel. These results are consistent with the pharmacokinetic and tissue distribution data as well as the proposed mechanism of action wherein the nanoparticles doped with docetaxel are designed to provide extended particle circulation times and controlled release of docetaxel from the nanoparticles so that particles can be targeted to and bind with a marker or target to increase the amount of docetaxel delivered to the tumor. -
EXAMPLE TABLE 4.1 Measured Docetaxel Concentration in Tumors Treated with Docetaxel Encapsulated in Nanoparticles and Conventional Docetaxel Docetaxel Concentration in the Tumor (ng/mg) Docetaxel Encapsulated Time (h) Conventional Docetaxel in Nanoparticles 2 12.9 ± 7.9 14.8 ± 6.5 12 3.6 ± 2.1 25.4 ± 15.1 - Male severe combined immunodeficiency (SCID) mice were subcutaneously inoculated with human LNCaP prostate cancer cells. Three to four weeks after inoculation, the mice were assigned to different treatment groups such that the average tumor volume in each group was 250 mm3. Subsequently, the mice were treated every other day (Q2D) for four doses, with an eight day holiday, followed by another four doses at the Q2D schedule.
- Average tumor volumes for each treatment group are shown in Example
FIG. 7 . Treatment with either conventional docetaxel or docetaxel encapsulated in nanoparticles resulted in appreciable reduction in tumor volume. Tumor volume reduction was greater in test subjects receiving docetaxel encapsulated in nanoparticles compared to conventional docetaxel. These results suggest that the increase in tumor docetaxel concentration in test subjects receiving nanoparticles doped with docetaxel, compared to conventional docetaxel, may result in a more pronounced cytotoxic effect. - Sixty Sprague-Dawley rats (30/sex) were assigned to 10 dose groups (3 rats/sex/group) and were administered a single dose of either docetaxel encapsulated in nanoparticles (5.7, 7.5, 10, 15 or 30 mg/kg body weight) or conventional docetaxel (5.7, 7.5, 10, 15 or 30 mg/kg body weight). The therapeutic compositions were administered by intravenous (IV) infusion over a 30-minute period on
Day 1, after which the test subjects were observed for 7 days prior to undergoing a gross necropsy. - All test subjects survived to their scheduled necropsy. Clinical observations considered to be potentially related to administration included piloerection, which appeared near the end of the 7 day observation period, and discharges from the nose and eyes. Piloerection was observed for one male rat dosed with 15 mg/kg of docetaxel encapsulated in nanoparticles, and for 5/9 male rats and 1/9 female rats dosed with 10 mg/kg of conventional docetaxel or higher. The nature and time of appearance of this clinical sign were consistent with toxicity that would be expected from cytotoxic drugs like docetaxel. Nasal and eye discharges appeared with a pattern that was unrelated to dose level, test article, sex of the animals, or time after dosing, and this clinical sign was considered to be possibly related to docetaxel and/or to stress from the dosing procedure. As shown in Example Table 6.1, male and female rats dosed with either conventional docetaxel or docetaxel encapsulated in nanoparticles showed generally minor deficits in body weight gain or actual body weight losses that were considered to be due to docetaxel toxicity. The no-adverse effect level (NOAEL) of nanoparticles doped with docetaxel in this study was considered to be 7.5 mg/kg.
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EXAMPLE TABLE 6.1 Comparison of Body Weight Changes in Males and Females Docetaxel Encapsulated Dose in Nanoparticles Conventional Docetaxel Sex (mg/kg) Body Weight Change (%) Body Weight Change (%) M 5.7 4.60 8.60 M 7.5 1.67 1.21 M 10 −3.15 −11.55 M 15 −6.23 −9.48 M 30 −7.16 −8.66 F 5.7 3.63 0.34 F 7.5 3.25 −0.11 F 10 −2.49 −0.17 F 15 −2.50 −6.86 F 30 −5.66 −5.89 - Similar to the procedure in Example 2, rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in
FIG. 2 and Example 14 having vincristine and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or vincristine alone. The release profiles are shown inFIG. 8 . - Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software. A comparison of the pharmacokinetics of the nanoparticles with vincristine alone is as follows:
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Comparison with vincristine alone Cmax (ng/mL) 69-fold ↑ t1/2 (hr) 1.8-fold ↓ AUCinf (hr*ng/mL) 312-fold ↑ Vz (mL/kg) 592-fold ↓ Cl (mL/hr/kg) 322-fold ↓ - Similar to the procedure in Example 2, rats were intravenously dosed with 0.5 mg/kg with either nanoparticles prepared as in
FIG. 2 and Example 15 having methotrexate and PLA-PEG, and no specific targeting moiety (passively targeted nanoparticles (PTNP); or methotrexate alone. The release profiles are shown inFIG. 9 . - Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software. A comparison of the pharmacokinetics of the nanoparticles with methotrexate alone is as follows:
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Comparison with methotrexate alone Cmax (ng/mL) 10-fold ↑ t1/2 (hr) 16-fold ↓ AUCinf (hr * ng/mL) 296-fold ↑ Vz (mL/kg) 19-fold ↓ Cl (mL/hr/kg) 302-fold ↓ - Similar to the procedure in Example 2, rats were intravenously dosed with 1.0 mg/kg with either nanoparticles prepared as in
FIG. 2 having paclitaxel and PLA-PEG (formulation C) and no specific targeting moiety (passively targeted nanoparticles (PTNP); or paclitaxel alone. The release profiles are shown inFIG. 10 . - Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software. A comparison of the pharmacokinetics of the nanoparticles with paclitaxel alone is as follows:
-
Comparison with paclitaxel alone Cmax (ng/mL) 297-fold ↑ t1/2 (hr) 3-fold ↓ AUCinf (hr * ng/mL) 600-fold ↑ Vz (mL/kg) 1512-fold ↓ Cl (mL/hr/kg) 516-fold ↓ - Similar to the procedure in Example 2, rats were intravenously dosed with 2.0 mg/kg with either nanoparticles prepared as in
FIG. 2 and Example 16, having rapamycin and PLA-PEG and no specific targeting moiety (passively targeted nanoparticles (PTNP); or rapamycin alone. The release profiles are shown inFIG. 11 . - Plasma samples were analyzed using LC/MS and the PK analysis was performed using WinNonlin software. A comparison of the pharmacokinetics of the nanoparticles with rapamcyin alone is as follows:
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Comparison with rapamcyin alone Cmax (ng/mL) 297-fold ↑ t1/2 (hr) 3-fold ↓ AUCinf (hr * ng/mL) 600-fold ↑ Vz (mL/kg) 1512-fold ↓ Cl (mL/hr/kg) 516-fold ↓ - Mice with MX-1 breast tumors were randomized into three groups, receiving docetaxel (3 mice), passively targeted nanoparticles (Formulation A, without a targeting moiety, PTNP), or Formulation A. The average tumor mass was 1.7 g (RSD 34%). Mice were then injected with 10 mg/kg of the test article, then euthanized 24 hours later and the tumors were removed and analyzed for docetaxel content using LC/MS/MS. Results are depicted in
FIG. 12 . The percent of injected dose in the tumor was 3% (for docetaxel alone), 30% for PTNP, and 30% Formulation A. - Naïve non human primates (3 male and 3 female) were administered docetaxel, docetaxel nanoparticles (Formulation A) or docetaxel nanoparticles (Formulation B: 43.25% PLA-PEG (16/5), 43.25% PLA (75 kDa), 10% docetaxel, 2.5% PLA-PEG-lys(urea)glu, prepared as in Example 14), using and following appropriate ethical guidelines at all times. 1 male and 1 female were used per dose group. The dosing day was 1 day and the formulations were administered by 30 minute IV infusion at 25 mg/m2 docetaxel or 50 mg/m2 docetaxel (animals were randomized and then dosed with 50 mg/m2 on day 29 and PK, hematology and clinical chemistry were measured for 21 days). At the end of the study, PK, hematology and clinical chemistry collected over a 21 day period were assessed.
FIG. 12 depicts the results of male (M) and female (F) PNP. A comparison of the pharmacokinetics of the nanoparticles of Formulation A (25 mg/m2 dose) with docetaxel alone is as follows: -
Comparison with docetaxel alone Cmax (ng/mL) 180-fold ↑ t1/2 (hr) 3-fold ↓ AUCinf (hr * ng/mL) 213-fold ↑ Vz (mL/kg) 617-fold ↓ Cl (mL/hr/kg) 212-fold ↓ - The pharmokinetics were as follows for each NHP group:
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25 mg/ m2 50 mg/m2 M F M F Cmax (ng/mL) 364 596 1210 835 Cmax/D 14.6 23.8 24.2 16.7 AUC (hr * ng/mL) 2553 2714 3285 3599 AUC/D 102 109 76.5 72 t1/2 (hr) 18 31 39 39 Vz (mL/m2) 253783 412186 743682 788340 Cl (mL/hr/m2) 9794 9213 13073 13893 -
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25 mg/ m2 50 mg/m2 M F M F Cmax (ng/mL) 89500 85500 95700 117000 Cmax/D 3580 3420 1914 2340 AUC 495408 627216 352778 748073 (hr * ng/mL) AUC/D 19816 25089 7056 14961 t1/2 (hr) 7.6 9.1 5.6 6.8 Vz (mL/m2) 554 526 1140 654 Cl (mL/hr/m2) 50 40 142 67 -
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25 mg/ m2 50 mg/m2 M F M F Cmax (ng/mL) 64500 101500 128000 116000 Cmax/D 2580 4060 2560 2320 AUC 956312 1442885 1960145 1395580 (hr * ng/mL) AUC/D 38252 57715 39203 27912 t1/2 (hr) 13.9 17.8 17.8 15.5 Vz (mL/m2) 525 445 657 803 Cl (mL/hr/m2) 26.1 17.3 25.5 35.8 - An organic phase is formed composed of a mixture of docetaxel (DTXL) and polymer (homopolymer, co-polymer, and co-polymer with ligand). The organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent. In order to achieve high drug loading, about 30% solids in the organic phase is used.
- The primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer. The rotor/stator yielded a homogeneous milky solution, while the stir bar produced a visibly larger coarse emulsion. It was observed that the stir bar method resulted in significant oil phase droplets adhering to the side of the feed vessel, suggesting that while the coarse emulsion size is not a process parameter critical to quality, it should be made suitably fine in order to prevent yield loss or phase separation. Therefore the rotor stator is used as the standard method of coarse emulsion formation, although a high speed mixer may be suitable at a larger scale.
- The primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer.
- After 2-3 passes the particle size was not significantly reduced, and successive passes can even cause a particle size increase. Organic phase was emulsified 5:1 O:W with standard aqueous phase, and multiple discreet passes were performed, quenching a small portion of emulsion after each pass. The indicated scale represents the total solids of the formulation.
- The effect of scale on particle size showed surprising scale dependence. The trend shows that in the 2-10 g batch size range, larger batches produce smaller particles. It has been demonstrated that this scale dependence is eliminated when considering greater than 10 g scale batches. The amount of solids used in the oil phase was about 30%.
FIGS. 8 and 9 depicts the effect of solids concentration on particle size and drug loading; with the exception of the 15-175 series, all batches are placebo. For placebo batches the value for % solids represents the % solids were drug present at the standard 20% w/w. - Table A summarizes the emulsification process parameters.
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TABLE A Parameter Value Coarse emulsion formation Rotor stator homogenizer Homogenizer feed pressure 4000-5000 psi per chamber Interaction chamber(s) 2 × 200 μm Z-chamber Number of homogenizer passes 2-3 passes Water phase 0.1% [sodium cholate] W:O ratio 5:1 [Solids] in oil phase 30% - The fine emulsion is then quenched by addition to deionized water at a given temperature under mixing. In the quench unit operation, the emulsion is added to a cold aqueous quench under agitation. This serves to extract a significant portion of the oil phase solvents, effectively hardening the nanoparticles for downstream filtration. Chilling the quench significantly improved drug encapsulation. The quench:emulsion ratio is approximately 5:1.
- A solution of 35% (wt %) of
Tween 80 is added to the quench to achieve approximately 2% Tween 80 overall After the emulsion is quenched a solution of Tween-80 is added which acts as a drug solubilizer, allowing for effective removal of unencapsulated drug during filtration. Table B indicates each of the quench process parameters. -
TABLE B Summary quench process parameters. Parameter Value Initial quench temperature <5° C. [Tween-80] solution 35% Tween-80:drug ratio 25:1 Q:E ratio 5:1 Quench hold/processing temp ≦5° C. (with current 5:1 Q:E ratio, 25:1 Tween-80:drug ratio) - The temperature must remain cold enough with a dilute enough suspension (low enough concentration of solvents) to remain below the Tg of the particles. If the Q:E ratio is not high enough, then the higher concentration of solvent plasticizes the particles and allows for drug leakage. Conversely, colder temperatures allow for high drug encapsulation at low Q:E ratios (to ˜3:1), making it possible to run the process more efficiently.
- The nanoparticles are then isolated through a tangential flow filtration process to concentrate the nanoparticle suspension and buffer exchange the solvents, free drug, and drug solubilizer from the quench solution into water. A regenerated cellulose membrane is used with with a molecular weight cutoffs (MWCO) of 300.
- A constant volume diafiltration (DF) is performed to remove the quench solvents, free drug and Tween-80. To perform a constant-volume DF, buffer is added to the retentate vessel at the same rate the filtrate is removed. The process parameters for the TFF operations are summarized in Table C. Crossflow rate refers to the rate of the solution flow through the feed channels and across the membrane. This flow provides the force to sweep away molecules that can foul the membrane and restrict filtrate flow. The transmembrane pressure is the force that drives the permeable molecules through the membrane.
-
TABLE C TFF Parameters Parameter Value Membrane Regenerated Material cellulose - Coarse Screen Membrane Molecular 300 kDa Weight Cut off Crossflow Rate 11 L/min/m2 Transmembrane 20 psid Pressure Concentration 30 mg/ml of Nanoparticle Suspension for Diafiltration Number of ≧15 (based Diavolumes on flux increase) Membrane ~1 m2/kg Area - The filtered nanoparticle slurry is then thermal cycled to an elevated temperature during workup. A small portion (typically 5-10%) of the encapsulated drug is released from the nanoparticles very quickly after its first exposure to 25° C. By exposing the nanoparticle slurry to elevated temperature during workup, ‘loosely encapsulated’ drug can be removed and improve the product stability at the expense of a small drop in drug loading.
- After the filtration process the nanoparticle suspension (
concentration 50 mg/ml), is passed through a sterilizing grade filter (0.2 μm absolute). Pre-filters are used to protect the sterilizing grade filter in order to use a reasonable filtration area/time for the process. Filtration flow rate is ˜1.3 L/min/m2. - The filtration train is Ertel Alsop Micromedia XL depth filter M953P membrane (0.2 μm Nominal); Pall SUPRAcap with Seitz EKSP depth filter media (0.1-0.3 μm Nominal); Pall Life Sciences Supor EKV 0.65/0.2 micron sterilizing grade PES filter. 0.2 m2 of filtration surface area per kg of nanoparticles for depth filters and 1.3 m2 of filtration surface area per kg of nanoparticles for the sterilizing grade filters can be used.
- The nanoparticle preparation protocol described in Example 12 was modified to produce slow release nanoparticles.
- A batch of nanoparticles was produced that incorporated a 50:50 ratio of 100 DL 7E PLA (see Table 1) with the 16/5 PLA-PEG copolymer. The addition of high molecular weight PLA is thought to decrease drug diffusion by increasing crystallinity, raising the glass transition temperature, or reducing drug solubility in the polymer.
-
TABLE 1 High Molecular Weight PLA Tested Molecular Weight Molecular Weight PLA Manufacturer (Mn) (Mw) 100 DL 7E Lakeshore Polymer 80 kDa 124 kDa - The addition of high molecular weight PLA resulted in larger particle size when all other formulation variables were kept constant. In order to obtain slow release nanoparticles with comparable sizes as nanoparticles prepared without the high molecular weight PLA, the concentration of solids in the oil phase was reduced and the concentration of sodium cholate in the water phase was increased. Table 2 illustrates the slow release nanoparticle formulation.
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TABLE 2 Slow Release Formulation Summary % Sodium Cholate in % Solids in Water % Drug Particle Polymers Used Oil Phase Phase Load Size (nm) 50% BI 16/5 PLA- PEG 20% 2.0% 11.7% 139.8 50 % Lakeshore 100 DL 7E PLA - Nanoparticle batches were prepared using the general procedure of Example 12, with 80% (w/w) Polymer-PEG or Polymer-PEG with homopolymer PLA at 40% (w/w) each, with a batch of % total solids of 5%, 15% and 30%. Solvents used were: 21% benzyl alcohol and 79% ethyl acetate (w/w). For each 2 gram batch size, 400 mg of drug was used and 1.6 g of 16-5 Polymer-PEG or 0.8 g of 16-5 Polymer-PEG+0.8 g of 10 kDa PLA (homopolymer) was used. The diblock polymer 16-5 PLA-PEG or PLGA-PEG (50:50 L:G) was used, and if used, the homopolymer: PLA with a Mn=6.5 kDa, Mw=10 kDa, and Mw/Mn=1.55.
- The organic phase (drug and polymer) is prepared in 2 g batches: To 20 mL scintillation vial add drug and polymer(s). The mass of solvents needed at % solids concentration is:: 5% solids: 7.98 g benzyl alcohol+30.02 g ethyl acetate; 30% solids: 0.98 g benzyl alcohol+3.69 g ethyl acetate
- An aqueous solution is prepared with 0.5% sodium cholate, 2% benzyl alcohol, and 4% ethyl acetate in water. Add to the bottle 7.5 g sodium cholate, 1402.5 g of DI water, 30 g of benzyl alcohol and 60 g of ethyl acetate, and mix on stir plate until dissolved.
- For the formation of emulsion, a ratio of aqueous phase to oil phase is 5:1. The organic phase is poured into the aqueous solution and homogenized using IKA for 10 seconds at room temperature to form course emulsion. The solution is fed through the homogenizer (110S) at 9 Kpsi (45 psi on gauge) for 2 discreet passes to form nanoemulsion.
- The emulsion is poured into quench (D.I. water) at <5° C. while stirring on stir plate. Ratio of quench to emulsion is 8:1. 35% (w/w)
Tween 80 is added in water to quench at ratio of 25:1Tween 80 to drug. The nanoparticles are concentrated through TFF and the quench is concentrated on TFF with 500 kDa Pall cassette (2 membrane) to ˜100 mL. Diafiltering is used using ˜20 diavolumes (2 liters) of cold DI water, and the volume is brought down to minimal volume then collect final slurry, ˜100 mL. The solids concentration of unfiltered final slurry is determined by the usingtared 20 mL scintillation vial and adding 4 mL final slurry and dry under vacuum on lyo/oven and the weight of nanoparticles in the 4 mL of slurry dried down is determined. Concentrated sucrose (0.666 g/g) is added to final slurry sample to attain 10% sucrose. - Solids concentration of 0.45 um filtered final slurry was determined by filtering about 5 mL of final slurry sample before addition of sucrose through 0.45 μm syringe filter; to tared 20 mL scintillation vial add 4 mL of filtered sample and dry under vacuum on lyo/oven.
- The remaining sample of unfiltered final slurry was frozen with sucrose.
-
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Composition Components by Wt.(%) mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/Vincristine 95/5 mPEG(5k)-lPLA(16K)/Vincristine 96/4 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 46/46/8 mPEG(5k)-lPLA(16K)/lPLA(16K)/Vincristine 47/47/6 - Analytical characterization of Vincristine Formulations:
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Encapsulation Efficiency Size (nm) Drug Load (%) (%) 103 4.4 21.8 110 4.6 22.8 115 4.2 20.8 146 8.3 41.6 98 6.0 30.0 - Drug was dissolved in the inner aqueous phase consisting of water with 1-arginine or NaOH used for solubilizing the drug. The polymer (16-5 PLA-PEG) was dissolved in the oil phase organic solvent system, such as dichloromethane (DCM) at 20% solid concentration. The outer aqueous phase consisted mainly of water with 1% sodium cholate (SC) as surfactant, unless noted otherwise. The w/o emulsion was prepared by adding the inner aqueous phase into the oil phase under rotor stator homogenization or sonication (using Branson Digital Sonifier) at a w/o ratio of 1:10. The coarse w/o/w emulsion was also prepared by adding the w/o emulsion into an outer aqueous phase under either rotor stator homogenization or sonication at o/w ratio of 1:10. The fine w/o/w emulsion was then prepared by processing the coarse emulsion through a Microfluidics high pressure homogenizer (M110S pneumatic) at 45000 psi with a 100 μm Z-interaction chamber. The fine emulsion was then quenched into cold DI water at 10:1 quench:emulsion ratio. These w/o, o/w and emulsion:quench ratios were maintained at 1:10 for all w/o/w experiments, unless noted otherwise. Polysorbate 80 (Tween 80) was then added as a process solubilizer to solubilize the unencapsulated drug. No drug precipitation was observed at a drug:
Tween 80 ratio of 1:200. The batch was then processed with ultrafiltration followed by diafiltration to remove solvents, unencapsulated drug and solubilizer. The particle size measurements were performed by Brookhaven DLS and/or Horiba laser diffraction. To determine drug load, slurry samples were analyzed by HPLC and solid concentration analysis. The slurry retains were then diluted with sucrose to 10% before freezing. All ratios listed are on a w/w basis, unless specified otherwise. - Using 16/5 PLA-PEG dissolved in ethyl acetate afforded particles between 77-85 nm in size at ≦6% solid concentration in an outer aqueous phase consisting of 1% SC in DI water. Emulsions were formed under sonication at 30% amplitude. Gel formation occurred in the initial w/o emulsion with ≧6% solid concentration. The inner aqueous phase MTX concentration was increased to 225 mg/ml using 1-arginine. The batch was made with 20% solids in the oil phase, consisting of 28/5 PLGA-PEG dissolved in DCM. Here, both the inner w/o and outer w/o/w emulsions were formed by rotor stator homogenization followed by 2 passes at 45 k psi using a high pressure homogenizer. The nanoparticle suspension was quenched in cold DI water followed by ultrafiltration/diafiltration work-up. HPLC and PSD analysis was used to determine that the drug load stayed at 0.38% for 131 nm particles.
- Three different batches can be prepared according to the general procedure with the following modifications; Inner aqueous phase MTX concentration was 225 mg/ml in 0.66N NaOH solution, i.e., a 1-arginine:MTX molar ratio of 1.45:1;
Span 80/Tween 80 surfactant mix (HLB=6.2) was used as the oil phase surfactant; Batch 55-101C: 16/5 PLA-PEG was used instead of 28/5 PLGA-PEG. The emulsion process for all three batches remained similar. The highest drug load was obtained for the 16/5 PLA-PEG batch at 2.23% while the drug load was 0.2% and 0.04% for other batches. - An organic phase is formed composed of a mixture of sirolimus and polymer (homopolymer, co-polymer, and co-polymer with ligand). The organic phase is mixed with an aqueous phase at approximately a 1:5 ratio (oil phase:aqueous phase) where the aqueous phase is composed of a surfactant and some dissolved solvent. In order to achieve high drug loading, about 30% solids in the organic phase is used. The primary, coarse emulsion is formed by the combination of the two phases under simple mixing or through the use of a rotor stator homogenizer.
- The primary emulsion is then formed into a fine emulsion through the use of a high pressure homogenizer. The process is continued as in Example 12.
- Representative Rapamycin (sirolimus) formulations:
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Drug Name Polymer Size (nm) Loading 5% Solid 16/5 PLA/PEG 123.1 3.61% 16/5 PLA/PEG + PLA 119.7 4.49% 15% Solid 16/5 PLA/PEG 82.1 4.40% 16/5 PLA/PEG + PLA 120.6 11.51% 23% Solid 16/5 PLA/PEG 88.1 7.40% 16/5 PLA/PEG + PLA 118.3 7.8% 30% Solid 16/5 PLA/PEG 88.5 10.26% 16/5 PLA/PEG + PLA 118.3 10.18% - Although the invention has been described in considerable detail with reference to certain preferred aspects thereof, other versions are possible. Therefore the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.
- References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.
- Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
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US14/922,755 Abandoned US20160045608A1 (en) | 2008-12-15 | 2015-10-26 | Long circulating nanoparticles for sustained release of therapeutic agents |
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Cited By (101)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090061010A1 (en) * | 2007-03-30 | 2009-03-05 | Massachusetts Institute Of Technology | Cancer cell targeting using nanoparticles |
US20100068286A1 (en) * | 2008-06-16 | 2010-03-18 | Greg Troiano | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100069426A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US20100104655A1 (en) * | 2008-06-16 | 2010-04-29 | Zale Stephen E | Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same |
US20100226986A1 (en) * | 2008-12-12 | 2010-09-09 | Amy Grayson | Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same |
US20110217377A1 (en) * | 2008-12-15 | 2011-09-08 | Zale Stephen E | Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents |
US8211473B2 (en) | 2009-12-11 | 2012-07-03 | Bind Biosciences, Inc. | Stable formulations for lyophilizing therapeutic particles |
US20130059946A1 (en) * | 2011-04-25 | 2013-03-07 | Jingxu Zhu | Biocompatible polymer nanoparticle coating composition and method of production thereof |
US8518963B2 (en) | 2009-12-15 | 2013-08-27 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
WO2013151666A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides for the production of biologics and proteins associated with human disease |
WO2013151736A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | In vivo production of proteins |
US8709483B2 (en) | 2006-03-31 | 2014-04-29 | Massachusetts Institute Of Technology | System for targeted delivery of therapeutic agents |
US20140199352A1 (en) * | 2013-01-14 | 2014-07-17 | Xerox Corporation | Porous nanoparticles produced by solvent-free emulsification |
WO2014152211A1 (en) | 2013-03-14 | 2014-09-25 | Moderna Therapeutics, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
WO2014152540A1 (en) | 2013-03-15 | 2014-09-25 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US8906381B2 (en) | 2008-10-12 | 2014-12-09 | Massachusetts Institute Of Technology | Immunonanotherapeutics that provide IGG humoral response without T-cell antigen |
US8932595B2 (en) | 2008-10-12 | 2015-01-13 | Massachusetts Institute Of Technology | Nicotine immunonanotherapeutics |
WO2015006747A2 (en) | 2013-07-11 | 2015-01-15 | Moderna Therapeutics, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use. |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2015034928A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
US20150118311A1 (en) * | 2012-05-04 | 2015-04-30 | Yale Universit | Highly Penetrative Nanocarriers for Treatment of CNS Disease |
WO2015075557A2 (en) | 2013-11-22 | 2015-05-28 | Mina Alpha Limited | C/ebp alpha compositions and methods of use |
US9217129B2 (en) | 2007-02-09 | 2015-12-22 | Massachusetts Institute Of Technology | Oscillating cell culture bioreactor |
WO2016014846A1 (en) | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of intrabodies |
US9267937B2 (en) | 2005-12-15 | 2016-02-23 | Massachusetts Institute Of Technology | System for screening particles |
US9314532B2 (en) | 2012-08-10 | 2016-04-19 | University Of North Texas Health Science Center | Drug delivery vehicle |
US9333179B2 (en) | 2007-04-04 | 2016-05-10 | Massachusetts Institute Of Technology | Amphiphilic compound assisted nanoparticles for targeted delivery |
US9381477B2 (en) | 2006-06-23 | 2016-07-05 | Massachusetts Institute Of Technology | Microfluidic synthesis of organic nanoparticles |
US9474717B2 (en) | 2007-10-12 | 2016-10-25 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US9492400B2 (en) | 2004-11-04 | 2016-11-15 | Massachusetts Institute Of Technology | Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals |
WO2017070626A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory virus vaccines |
WO2017070622A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory syncytial virus vaccine |
WO2017070613A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2017070601A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Nucleic acid vaccines for varicella zoster virus (vzv) |
WO2017070620A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Broad spectrum influenza virus vaccine |
WO2017070623A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Herpes simplex virus vaccine |
US20170138387A1 (en) * | 2013-11-22 | 2017-05-18 | Sannohashi Corporation | Bolt, nut, and strain measurement system |
WO2017112943A1 (en) | 2015-12-23 | 2017-06-29 | Modernatx, Inc. | Methods of using ox40 ligand encoding polynucleotides |
WO2017120612A1 (en) | 2016-01-10 | 2017-07-13 | Modernatx, Inc. | Therapeutic mrnas encoding anti ctla-4 antibodies |
US9877923B2 (en) | 2012-09-17 | 2018-01-30 | Pfizer Inc. | Process for preparing therapeutic nanoparticles |
US9895378B2 (en) | 2014-03-14 | 2018-02-20 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same |
WO2018213731A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
WO2018213789A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Modified messenger rna comprising functional rna elements |
WO2018232006A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
US20180369231A1 (en) * | 2017-06-22 | 2018-12-27 | SNBioScience Inc. | Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same |
WO2019048631A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Hnf4a sarna compositions and methods of use |
WO2019048645A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
WO2019104160A2 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
WO2019104195A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia |
WO2019104152A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
WO2019136241A1 (en) | 2018-01-05 | 2019-07-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
WO2019197845A1 (en) | 2018-04-12 | 2019-10-17 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2019200171A1 (en) | 2018-04-11 | 2019-10-17 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
WO2019226650A1 (en) | 2018-05-23 | 2019-11-28 | Modernatx, Inc. | Delivery of dna |
WO2020023390A1 (en) | 2018-07-25 | 2020-01-30 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
US10548881B2 (en) | 2016-02-23 | 2020-02-04 | Tarveda Therapeutics, Inc. | HSP90 targeted conjugates and particles and formulations thereof |
WO2020047201A1 (en) | 2018-09-02 | 2020-03-05 | Modernatx, Inc. | Polynucleotides encoding very long-chain acyl-coa dehydrogenase for the treatment of very long-chain acyl-coa dehydrogenase deficiency |
WO2020056155A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease |
WO2020056147A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding glucose-6-phosphatase for the treatment of glycogen storage disease |
WO2020056239A1 (en) | 2018-09-14 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2020069169A1 (en) | 2018-09-27 | 2020-04-02 | Modernatx, Inc. | Polynucleotides encoding arginase 1 for the treatment of arginase deficiency |
WO2020097409A2 (en) | 2018-11-08 | 2020-05-14 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
WO2020208361A1 (en) | 2019-04-12 | 2020-10-15 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2020227642A1 (en) | 2019-05-08 | 2020-11-12 | Modernatx, Inc. | Compositions for skin and wounds and methods of use thereof |
WO2020263985A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Messenger rna comprising functional rna elements and uses thereof |
WO2020263883A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Endonuclease-resistant messenger rna and uses thereof |
US20200405642A1 (en) * | 2018-02-26 | 2020-12-31 | AnTolRx, Inc. | Tolerogenic liposomes and methods of use thereof |
WO2021061707A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | Compositions and methods for modulating apolipoprotein b (apob) gene expression |
WO2021061815A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR MODULATING HEPATOCYTE NUCLEAR FACTOR 4-ALPHA (HNF4α) GENE EXPRESSION |
US10967039B2 (en) | 2013-05-28 | 2021-04-06 | Sintef Tto As | Process for preparing stealth nanoparticles |
WO2021183720A1 (en) | 2020-03-11 | 2021-09-16 | Omega Therapeutics, Inc. | Compositions and methods for modulating forkhead box p3 (foxp3) gene expression |
WO2021247507A1 (en) | 2020-06-01 | 2021-12-09 | Modernatx, Inc. | Phenylalanine hydroxylase variants and uses thereof |
WO2021252354A1 (en) | 2020-06-12 | 2021-12-16 | University Of Rochester | ENCODING AND EXPRESSION OF ACE-tRNAs |
WO2022104131A1 (en) | 2020-11-13 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
US11345932B2 (en) | 2018-05-16 | 2022-05-31 | Synthego Corporation | Methods and systems for guide RNA design and use |
WO2022122872A1 (en) | 2020-12-09 | 2022-06-16 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2022204380A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof |
WO2022204369A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia |
WO2022204371A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof |
WO2022204370A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency |
WO2022204390A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof |
WO2022200810A1 (en) | 2021-03-26 | 2022-09-29 | Mina Therapeutics Limited | Tmem173 sarna compositions and methods of use |
EP4074834A1 (en) | 2012-11-26 | 2022-10-19 | ModernaTX, Inc. | Terminally modified rna |
WO2022240806A1 (en) | 2021-05-11 | 2022-11-17 | Modernatx, Inc. | Non-viral delivery of dna for prolonged polypeptide expression in vivo |
WO2022266083A2 (en) | 2021-06-15 | 2022-12-22 | Modernatx, Inc. | Engineered polynucleotides for cell-type or microenvironment-specific expression |
WO2022271776A1 (en) | 2021-06-22 | 2022-12-29 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2023283359A2 (en) | 2021-07-07 | 2023-01-12 | Omega Therapeutics, Inc. | Compositions and methods for modulating secreted frizzled receptor protein 1 (sfrp1) gene expression |
EP4144378A1 (en) | 2011-12-16 | 2023-03-08 | ModernaTX, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
EP4159741A1 (en) | 2014-07-16 | 2023-04-05 | ModernaTX, Inc. | Method for producing a chimeric polynucleotide encoding a polypeptide having a triazole-containing internucleotide linkage |
WO2023056044A1 (en) | 2021-10-01 | 2023-04-06 | Modernatx, Inc. | Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023104964A1 (en) | 2021-12-09 | 2023-06-15 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2023150753A1 (en) | 2022-02-07 | 2023-08-10 | University Of Rochester | Optimized sequences for enhanced trna expression or/and nonsense mutation suppression |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023055998A3 (en) * | 2021-09-30 | 2023-09-14 | The Trustees Of Princeton University | Dna valency sorting chromatography |
WO2023183909A2 (en) | 2022-03-25 | 2023-09-28 | Modernatx, Inc. | Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia |
WO2023196399A1 (en) | 2022-04-06 | 2023-10-12 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding argininosuccinate lyase for the treatment of argininosuccinic aciduria |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
US11884918B2 (en) | 2019-01-25 | 2024-01-30 | Synthego Corporation | Systems and methods for modulating CRISPR activity |
WO2024026254A1 (en) | 2022-07-26 | 2024-02-01 | Modernatx, Inc. | Engineered polynucleotides for temporal control of expression |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011084518A2 (en) * | 2009-12-15 | 2011-07-14 | Bind Biosciences, Inc. | Therapeutic polymeric nanoparticles comprising corticosteroids and methods of making and using same |
JP5898627B2 (en) * | 2009-12-15 | 2016-04-06 | バインド セラピューティックス インコーポレイテッド | Therapeutic polymer nanoparticles containing epothilone and methods of making and using the same |
US8822663B2 (en) | 2010-08-06 | 2014-09-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
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WO2012068531A2 (en) | 2010-11-18 | 2012-05-24 | The General Hospital Corporation | Novel compositions and uses of anti-hypertension agents for cancer therapy |
US9327037B2 (en) | 2011-02-08 | 2016-05-03 | The Johns Hopkins University | Mucus penetrating gene carriers |
AU2012236099A1 (en) | 2011-03-31 | 2013-10-03 | Moderna Therapeutics, Inc. | Delivery and formulation of engineered nucleic acids |
CA2834571A1 (en) | 2011-04-29 | 2012-11-01 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers for inducing regulatory b cells |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
DE19216461T1 (en) | 2011-10-03 | 2021-10-07 | Modernatx, Inc. | MODIFIED NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS AND USES THEREOF |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US10568975B2 (en) | 2013-02-05 | 2020-02-25 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
WO2014179762A1 (en) | 2013-05-03 | 2014-11-06 | Selecta Biosciences, Inc. | Tolerogenic synthetic nanocarriers and therapeutic macromolecules for reduced or enhanced pharmacodynamic effects |
US20140378083A1 (en) * | 2013-06-25 | 2014-12-25 | Plantronics, Inc. | Device Sensor Mode to Identify a User State |
MX2016000131A (en) * | 2013-06-28 | 2016-06-15 | Bind Therapeutics Inc | Docetaxel polymeric nanoparticles for cancer treatment. |
JP2016531112A (en) * | 2013-07-25 | 2016-10-06 | ネムコア メディカル イノベーションズ インコーポレイテッド | Nanoemulsions of hydrophobic platinum derivatives |
SI3311845T1 (en) | 2013-09-16 | 2020-06-30 | Astrazeneca Ab | Therapeutic polymeric nanoparticles and methods of making and using same |
CN103446060B (en) * | 2013-09-22 | 2015-09-02 | 上海市第八人民医院 | Carry Docetaxel sativum agglutinin and preparation method, pisum sativum agglutinin method of modifying and application |
WO2015048744A2 (en) | 2013-09-30 | 2015-04-02 | Moderna Therapeutics, Inc. | Polynucleotides encoding immune modulating polypeptides |
EA201690675A1 (en) | 2013-10-03 | 2016-08-31 | Модерна Терапьютикс, Инк. | POLYNUCLEOTES ENCODING THE RECEPTOR OF LOW DENSITY LIPOPROTEINS |
AU2014348683B2 (en) | 2013-11-18 | 2020-11-05 | Rubius Therapeutics, Inc. | Synthetic membrane-receiver complexes |
EP3079664A4 (en) * | 2013-12-10 | 2017-06-28 | The Regents of The University of California | Regionally activated drug delivery nanoparticles |
CN106456744A (en) | 2014-04-01 | 2017-02-22 | 鲁比厄斯治疗法股份有限公司 | Methods and compositions for immunomodulation |
US10335500B2 (en) | 2014-05-12 | 2019-07-02 | The Johns Hopkins University | Highly stable biodegradable gene vector platforms for overcoming biological barriers |
WO2016020901A1 (en) | 2014-08-07 | 2016-02-11 | Acerta Pharma B.V. | Methods of treating cancers, immune and autoimmune diseases, and inflammatory diseases based on btk occupancy and btk resynthesis rate |
MX2017002935A (en) | 2014-09-07 | 2017-05-30 | Selecta Biosciences Inc | Methods and compositions for attenuating exon skipping anti-viral transfer vector immune responses. |
EP3906918B1 (en) * | 2014-11-05 | 2024-01-03 | Selecta Biosciences, Inc. | Methods and compositions related to synthetic nanocarriers with rapamycin in a stable, super-saturated state |
EP3250184A1 (en) | 2015-01-27 | 2017-12-06 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
PT3350157T (en) | 2015-09-17 | 2022-03-18 | Modernatx Inc | Compounds and compositions for intracellular delivery of therapeutic agents |
CA2998504C (en) | 2015-09-21 | 2023-06-20 | Teva Pharmaceuticals International Gmbh | Sustained release olanzapine formulations |
LT3386484T (en) | 2015-12-10 | 2022-06-10 | Modernatx, Inc. | Compositions and methods for delivery of therapeutic agents |
WO2017106630A1 (en) | 2015-12-18 | 2017-06-22 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
US10799463B2 (en) | 2015-12-22 | 2020-10-13 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
CA3055936A1 (en) | 2017-03-11 | 2018-09-20 | Selecta Biosciences, Inc. | Methods and compositions related to combined treatment with anti-inflammatories and synthetic nanocarriers comprising an immunosuppressant |
US11203569B2 (en) | 2017-03-15 | 2021-12-21 | Modernatx, Inc. | Crystal forms of amino lipids |
WO2018170306A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
AU2018238136A1 (en) | 2017-03-20 | 2019-11-07 | Teva Pharmaceuticals International Gmbh | Sustained release olanzapine formulations |
EP3641766A4 (en) * | 2017-06-20 | 2021-03-17 | Tarveda Therapeutics, Inc. | Hsp90 targeted conjugates and particle formulations thereof |
EP3773477A1 (en) | 2018-04-03 | 2021-02-17 | Vaxess Technologies, Inc. | Microneedle comprising silk fibroin applied to a dissolvable base |
RU2681933C1 (en) * | 2018-11-28 | 2019-03-14 | Федеральное государственное бюджетное учреждение "Национальный исследовательский центр "Курчатовский институт" | Method for obtaining polymeric anti-tumor particles in flow microreactor and lyophilisate based on them |
US11179334B1 (en) * | 2019-02-04 | 2021-11-23 | Florida A&M University | Targeted carriers for tacrolimus for ocular inflammation |
EP4031524A1 (en) | 2019-09-19 | 2022-07-27 | ModernaTX, Inc. | Branched tail lipid compounds and compositions for intracellular delivery of therapeutic agents |
CN112294974A (en) * | 2020-11-18 | 2021-02-02 | 西安组织工程与再生医学研究所 | Drug-loaded microparticle with multistage sustained and controlled release effects and preparation method thereof |
US20240100012A1 (en) | 2021-01-18 | 2024-03-28 | Mark Hasleton | Pharmaceutical dosage form |
US11524023B2 (en) | 2021-02-19 | 2022-12-13 | Modernatx, Inc. | Lipid nanoparticle compositions and methods of formulating the same |
CA3227324A1 (en) | 2021-07-06 | 2023-01-12 | Mark Hasleton | Treatment of serotonin reuptake inhibitor withdrawal syndrome |
WO2023250117A2 (en) | 2022-06-24 | 2023-12-28 | Vaxess Technologies, Inc. | Applicator for medicament patch |
Citations (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
US5578325A (en) * | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US5766635A (en) * | 1991-06-28 | 1998-06-16 | Rhone-Poulenc Rorer S.A. | Process for preparing nanoparticles |
US6007845A (en) * | 1994-07-22 | 1999-12-28 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US6139870A (en) * | 1995-12-19 | 2000-10-31 | Aventis Pharma Sa | Stabilized nanoparticles which are filterable under sterile conditions |
US6254890B1 (en) * | 1997-12-12 | 2001-07-03 | Massachusetts Institute Of Technology | Sub-100nm biodegradable polymer spheres capable of transporting and releasing nucleic acids |
US20010008998A1 (en) * | 1996-05-15 | 2001-07-19 | Masato Tamaki | Business processing system employing a notice board business system database and method of processing the same |
US6265609B1 (en) * | 1998-07-06 | 2001-07-24 | Guilford Pharmaceuticals Inc. | Thio-substituted pentanedioic acid derivatives |
US6346274B1 (en) * | 1995-03-10 | 2002-02-12 | Roche Diagnostics Gmbh | Polypeptide-containing pharmaceutical forms of administration in the form of microparticles and method for the preparation thereof |
US20020045582A1 (en) * | 1997-12-31 | 2002-04-18 | Alexey L. Margolin | Stabilized protein crystals formulations containing them and methods of making them |
US6395718B1 (en) * | 1998-07-06 | 2002-05-28 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of inhibiting angiogenesis using naaladase inhibitors |
US20020119916A1 (en) * | 2000-12-22 | 2002-08-29 | Hassan Emadeldin M. | Elemental nanoparticles of substantially water insoluble materials |
US6528499B1 (en) * | 2000-04-27 | 2003-03-04 | Georgetown University | Ligands for metabotropic glutamate receptors and inhibitors of NAALADase |
US20030143184A1 (en) * | 2000-05-17 | 2003-07-31 | Min-Hyo Seo | Stable polymeric micelle-type drug composition and method for the preparation thereof |
US20030232887A1 (en) * | 2002-04-10 | 2003-12-18 | Johnson Douglas Giles | Preparation and use of a stable formulation of allosteric effector compounds |
US20030235619A1 (en) * | 2001-12-21 | 2003-12-25 | Christine Allen | Polymer-lipid delivery vehicles |
US20040054190A1 (en) * | 2002-01-10 | 2004-03-18 | Johns Hopkins University | Imaging agents and methods of imaging NAALADase or PSMA |
US20040071768A1 (en) * | 1999-04-01 | 2004-04-15 | Inex Pharmaceuticals Corporation | Compositions and methods for treating cancer |
US20040086544A1 (en) * | 1999-09-30 | 2004-05-06 | Chienna B.V. | Polymers with bioactive agents |
US20040185170A1 (en) * | 2003-03-21 | 2004-09-23 | Shubha Chungi | Method for coating drug-containing particles and formulations and dosage units formed therefrom |
WO2004084871A1 (en) * | 2003-03-26 | 2004-10-07 | Ltt Bio-Pharma Co., Ltd. | Intravenous nanoparticles for targenting drug delivery and sustained drug release |
US20040219224A1 (en) * | 2001-06-21 | 2004-11-04 | Kirill Yakovlevsky | Spherical protein particles and methods for making and using them |
US20040220081A1 (en) * | 2002-10-30 | 2004-11-04 | Spherics, Inc. | Nanoparticulate bioactive agents |
US20040247680A1 (en) * | 2003-06-06 | 2004-12-09 | Farokhzad Omid C. | Targeted delivery of controlled release polymer systems |
US20040247624A1 (en) * | 2003-06-05 | 2004-12-09 | Unger Evan Charles | Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility |
US6841547B2 (en) * | 2003-02-28 | 2005-01-11 | Albert Einstein College Of Medicine Of Yeshevia University | Method for decreasing low density lipoprotein |
US20050037086A1 (en) * | 1999-11-19 | 2005-02-17 | Zycos Inc., A Delaware Corporation | Continuous-flow method for preparing microparticles |
US6875886B2 (en) * | 2001-02-07 | 2005-04-05 | Beth Israel Deaconess Medical Center, Inc. | Modified PSMA ligands and uses related thereto |
US6890950B2 (en) * | 2002-04-23 | 2005-05-10 | Case Western Reserve University | Lapachone delivery systems, compositions and uses related thereto |
US6902743B1 (en) * | 1995-05-22 | 2005-06-07 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive material(s) encapuslated within a biodegradable-bio-compatable polymeric matrix |
US20050136258A1 (en) * | 2003-12-22 | 2005-06-23 | Shuming Nie | Bioconjugated nanostructures, methods of fabrication thereof, and methods of use thereof |
US20050142205A1 (en) * | 2003-07-18 | 2005-06-30 | Julia Rashba-Step | Methods for encapsulating small spherical particles prepared by controlled phase separation |
US20050256071A1 (en) * | 2003-07-15 | 2005-11-17 | California Institute Of Technology | Inhibitor nucleic acids |
US20050266067A1 (en) * | 2004-03-02 | 2005-12-01 | Shiladitya Sengupta | Nanocell drug delivery system |
US20060002971A1 (en) * | 2004-07-01 | 2006-01-05 | Yale University | Methods of treatment with drug loaded polymeric materials |
US20060057219A1 (en) * | 2002-05-24 | 2006-03-16 | Nanocarrier Co., Ltd. | Method for preparing a polymer micelle pharmaceutical preparation containing drug for injection |
US20060110460A1 (en) * | 2001-10-10 | 2006-05-25 | Eulalia Ferret | Prolonged release biodegradable microspheres and method for preparing same |
US20060165987A1 (en) * | 2002-04-05 | 2006-07-27 | Patrice Hildgen | Stealthy polymeric biodegradable nanospheres and uses thereof |
US20070031402A1 (en) * | 2005-08-03 | 2007-02-08 | Immunogen Inc. | Immunoconjugate formulations |
US20070043066A1 (en) * | 2005-07-11 | 2007-02-22 | Wyeth | Glutamate aggrecanase inhibitors |
US20070041901A1 (en) * | 2002-06-18 | 2007-02-22 | Diener John L | Stabilized aptamers to PSMA and their use as prostate cancer therapeutics |
US20070053845A1 (en) * | 2004-03-02 | 2007-03-08 | Shiladitya Sengupta | Nanocell drug delivery system |
US20070154554A1 (en) * | 2005-12-29 | 2007-07-05 | Robert Burgermeister | Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same |
US20080057102A1 (en) * | 2006-08-21 | 2008-03-06 | Wouter Roorda | Methods of manufacturing medical devices for controlled drug release |
US20080081074A1 (en) * | 2006-05-15 | 2008-04-03 | Massachusetts Institute Of Technology | Polymers for functional particles |
US20080124400A1 (en) * | 2004-06-24 | 2008-05-29 | Angiotech International Ag | Microparticles With High Loadings Of A Bioactive Agent |
US20080193381A1 (en) * | 2006-11-08 | 2008-08-14 | Molecular Insight Pharmaceuticals, Inc. | Heterodimers of glutamic acid |
US7422902B1 (en) * | 1995-06-07 | 2008-09-09 | The University Of British Columbia | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US20090053315A1 (en) * | 2007-08-21 | 2009-02-26 | Board Of Regents, The University Of Texas System | Thermo-Kinetic Mixing for Pharmaceutical Applications |
US20090053293A1 (en) * | 2005-09-09 | 2009-02-26 | Beijing Diacrid Medical Technology Co., Ltd. | Nano Anticancer Micelles of Vinca Alkaloids Entrapped in Polyethylene Glycolylated Phospholipids |
US20090061009A1 (en) * | 2007-08-29 | 2009-03-05 | Joseph Schwarz | Composition and Method of Treatment of Bacterial Infections |
US20090061010A1 (en) * | 2007-03-30 | 2009-03-05 | Massachusetts Institute Of Technology | Cancer cell targeting using nanoparticles |
US20090074828A1 (en) * | 2007-04-04 | 2009-03-19 | Massachusetts Institute Of Technology | Poly(amino acid) targeting moieties |
US20090074753A1 (en) * | 2004-10-14 | 2009-03-19 | Lynch Samuel E | Platelet-derived growth factor compositions and methods of use thereof |
US20090155349A1 (en) * | 2006-02-23 | 2009-06-18 | Jonathan Daniel Heller | Methods of treating influenza viral infections |
US20090170753A1 (en) * | 2006-07-26 | 2009-07-02 | Christian Welz | Capsofungin formulations |
US20090306120A1 (en) * | 2007-10-23 | 2009-12-10 | Florencia Lim | Terpolymers containing lactide and glycolide |
US20090317479A1 (en) * | 2005-12-26 | 2009-12-24 | Tsutomu Ishihara | Nanoparticles containing water-soluble non-peptide low-molecular weight drug |
US20100040537A1 (en) * | 2008-07-08 | 2010-02-18 | Abbott Laboratories | Prostaglandin E2 Binding Proteins and Uses Thereof |
US20100068285A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100087337A1 (en) * | 2008-09-10 | 2010-04-08 | Bind Biosciences, Inc. | High Throughput Fabrication of Nanoparticles |
US20100104655A1 (en) * | 2008-06-16 | 2010-04-29 | Zale Stephen E | Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same |
US20100226986A1 (en) * | 2008-12-12 | 2010-09-09 | Amy Grayson | Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same |
US20100316725A1 (en) * | 2009-05-27 | 2010-12-16 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US20110159079A1 (en) * | 2002-10-29 | 2011-06-30 | Zhili Li | High Delivery Rates for Lipid Based Drug Formulations, and Methods of Treatment Thereof |
US20110217377A1 (en) * | 2008-12-15 | 2011-09-08 | Zale Stephen E | Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents |
US8034765B2 (en) * | 2005-08-31 | 2011-10-11 | Abraxis Bioscience, Llc | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
US20110275704A1 (en) * | 2009-12-11 | 2011-11-10 | Greg Troiano | Stable Formulations for Lyophilizing Therapeutic Particles |
US20110294717A1 (en) * | 2009-12-15 | 2011-12-01 | Ali Mir M | Therapeutic Polymeric Nanoparticle Compositions with High Glass Transition Temperature or High Molecular Weight Copolymers |
Family Cites Families (88)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0394265B1 (en) | 1987-07-29 | 1994-11-02 | The Liposome Company, Inc. | Method for size separation of particles |
US5542935A (en) | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
WO1993011785A1 (en) * | 1991-12-09 | 1993-06-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Stabilized parathyroid hormone composition |
US5302401A (en) * | 1992-12-09 | 1994-04-12 | Sterling Winthrop Inc. | Method to reduce particle size growth during lyophilization |
GB9412273D0 (en) | 1994-06-18 | 1994-08-10 | Univ Nottingham | Administration means |
DE69630514D1 (en) | 1995-01-05 | 2003-12-04 | Univ Michigan | SURFACE-MODIFIED NANOPARTICLES AND METHOD FOR THEIR PRODUCTION AND USE |
JPH09208494A (en) * | 1995-11-30 | 1997-08-12 | Kanebo Ltd | Fine particle formulation |
US5792477A (en) | 1996-05-07 | 1998-08-11 | Alkermes Controlled Therapeutics, Inc. Ii | Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent |
US8038994B2 (en) * | 1996-05-15 | 2011-10-18 | Quest Pharmatech Inc. | Combination therapy for treating disease |
JP2942508B2 (en) | 1997-01-14 | 1999-08-30 | 順也 藤森 | Temperature sensitive sustained release base and temperature sensitive sustained release system |
US6201072B1 (en) * | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
CA2335852A1 (en) | 1998-06-30 | 2000-01-06 | Subodh Shah | Thermosensitive biodegradable hydrogels for sustained delivery of biologically active agents |
KR100274842B1 (en) | 1998-10-01 | 2001-03-02 | 김효근 | Sustained-release Drug Release System of Retinoic Acid Using Microspheres |
DE19856432A1 (en) | 1998-12-08 | 2000-06-15 | Basf Ag | Nanoparticulate core-shell systems and their use in pharmaceutical and cosmetic preparations |
US6194006B1 (en) | 1998-12-30 | 2001-02-27 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of microparticles having a selected release profile |
US6136846A (en) * | 1999-10-25 | 2000-10-24 | Supergen, Inc. | Formulation for paclitaxel |
KR100416242B1 (en) * | 1999-12-22 | 2004-01-31 | 주식회사 삼양사 | Liquid composition of biodegradable block copolymer for drug delivery and process for the preparation thereof |
US6890946B2 (en) | 1999-12-23 | 2005-05-10 | Indiana University Research And Technology Corporation | Use of parthenolide to inhibit cancer |
US6495164B1 (en) | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
KR100418916B1 (en) * | 2000-11-28 | 2004-02-14 | 한국과학기술원 | Process for Preparing Sustained Release Form of Micelle Employing Conjugate of Anticancer Drug and Biodegradable Polymer |
KR100446101B1 (en) | 2000-12-07 | 2004-08-30 | 주식회사 삼양사 | Sustained delivery composition for poorly water soluble drugs |
JP2004516262A (en) | 2000-12-21 | 2004-06-03 | ネクター セラピューティクス | Induced phase transition method for the production of microparticles containing hydrophilic activators |
CA2431888C (en) * | 2000-12-27 | 2010-06-01 | Ares Trading S.A. | Amphiphilic lipid nanoparticles for peptide and/or protein incorporation |
AU2002338336A1 (en) | 2001-04-03 | 2002-10-21 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
US7498045B2 (en) * | 2001-08-31 | 2009-03-03 | Thomas M. S. Chang | Biodegradable polymeric nanocapsules and uses thereof |
US6592899B2 (en) * | 2001-10-03 | 2003-07-15 | Macromed Incorporated | PLA/PLGA oligomers combined with block copolymers for enhancing solubility of a drug in water |
WO2003055469A1 (en) | 2001-12-21 | 2003-07-10 | Celator Technologies Inc. | Improved polymer-lipid delivery vehicles |
EP1478343B1 (en) | 2001-10-15 | 2017-03-22 | Crititech, Inc. | Compositions and methods for delivery of poorly water soluble drugs and methods of treatment |
EP1578193A4 (en) | 2002-12-23 | 2011-06-15 | Vical Inc | Method for freeze-drying nucleic acid/block copolymer/cationic surfactant complexes |
WO2004084869A1 (en) * | 2003-03-26 | 2004-10-07 | Egalet A/S | Matrix compositions for controlled delivery of drug substances |
AU2004228008B2 (en) | 2003-04-03 | 2008-11-06 | Jessie L.-S. Au | Tumor-targeting drug-loaded particles |
KR100534033B1 (en) | 2003-07-12 | 2005-12-08 | 주식회사 피스포스 | Pumping means of shoes |
ES2741576T3 (en) | 2003-07-23 | 2020-02-11 | Evonik Corp | Controlled release compositions |
JP2007504259A (en) | 2003-09-02 | 2007-03-01 | ノバルティス アクチエンゲゼルシャフト | Cancer treatment with epothilone |
US7311901B2 (en) * | 2003-10-10 | 2007-12-25 | Samyang Corporation | Amphiphilic block copolymer and polymeric composition comprising the same for drug delivery |
US8043631B2 (en) * | 2004-04-02 | 2011-10-25 | Au Jessie L S | Tumor targeting drug-loaded particles |
JP2006131577A (en) | 2004-11-09 | 2006-05-25 | Ltt Bio-Pharma Co Ltd | Method for preparing nanoparticle having different particle diameters and containing sealed medicine and nanoparticle obtained by the method |
KR20070104574A (en) | 2004-12-30 | 2007-10-26 | 신벤션 아게 | Combination comprising an agent providing a signal, an implant material and a drug |
WO2006093991A1 (en) | 2005-03-02 | 2006-09-08 | The Cleveland Clinic Foundation | Compounds which bind psma and uses thereof |
CA2603081C (en) | 2005-04-04 | 2013-09-03 | Sinexus, Inc. | Device and methods for treating paranasal sinus conditions |
JP2006321763A (en) | 2005-05-20 | 2006-11-30 | Hosokawa Funtai Gijutsu Kenkyusho:Kk | Biocompatibilie nanoparticle and method for production of the same |
US20110182805A1 (en) | 2005-06-17 | 2011-07-28 | Desimone Joseph M | Nanoparticle fabrication methods, systems, and materials |
US20090022806A1 (en) * | 2006-12-22 | 2009-01-22 | Mousa Shaker A | Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists and formulations and uses thereof |
US20080267876A1 (en) * | 2005-09-20 | 2008-10-30 | Yissum Research Development Company | Nanoparticles for Targeted Delivery of Active Agent |
US9393215B2 (en) | 2005-12-02 | 2016-07-19 | Novartis Ag | Nanoparticles for use in immunogenic compositions |
CA2550702A1 (en) * | 2006-03-24 | 2007-09-24 | Kensuke Egashira | Organic compounds |
DE102006013531A1 (en) * | 2006-03-24 | 2007-09-27 | Lts Lohmann Therapie-Systeme Ag | Drug delivery system, useful for supplying active substance to central nervous system of a mammal over the blood-brain barrier, comprises: nanoparticles of poly(DL-lactide-co-glycolide) and pharmaceutical substance e.g. cytostatic agent |
ES2776100T3 (en) * | 2006-03-31 | 2020-07-29 | Massachusetts Inst Technology | System for targeted delivery of therapeutic agents |
EP2056793A4 (en) | 2006-07-31 | 2011-08-17 | Neurosystec Corp | Free base gacyclidine nanoparticles |
US20100144845A1 (en) | 2006-08-04 | 2010-06-10 | Massachusetts Institute Of Technology | Oligonucleotide systems for targeted intracellular delivery |
WO2008038944A1 (en) * | 2006-09-26 | 2008-04-03 | Samyang Corporation | Submicron nanoparticle of poorly water soluble camptothecin derivatives and process for preparation thereof |
US20100303723A1 (en) | 2006-11-20 | 2010-12-02 | Massachusetts Institute Of Technology | Drug delivery systems using fc fragments |
CN1957911A (en) | 2006-12-01 | 2007-05-09 | 济南康泉医药科技有限公司 | Controlled release formulation for anti entity tumour |
CN101433520A (en) | 2006-12-12 | 2009-05-20 | 济南帅华医药科技有限公司 | Anticancer sustained-release agent containing epothilone |
CN1969818A (en) | 2006-12-12 | 2007-05-30 | 济南帅华医药科技有限公司 | Anticancer sustained release injection containing epothilone derivatives |
CN1961864A (en) | 2006-12-12 | 2007-05-16 | 济南帅华医药科技有限公司 | Anticancer composition |
CN1969816A (en) | 2006-12-12 | 2007-05-30 | 济南帅华医药科技有限公司 | Anticancer sustained release agent containing epothilone |
CN101396340A (en) | 2006-12-12 | 2009-04-01 | 济南帅华医药科技有限公司 | Anti-cancer sustained-released injection containing epothilone derivate |
CN101396342A (en) | 2006-12-12 | 2009-04-01 | 济南帅华医药科技有限公司 | Anti-cancer sustained-released injection containing epothilone derivate |
US20100015050A1 (en) * | 2006-12-21 | 2010-01-21 | Wayne State University | Peg and targeting ligands on nanoparticle surface |
JP2008162904A (en) * | 2006-12-27 | 2008-07-17 | Ltt Bio-Pharma Co Ltd | Therapeutic agent for bronchial asthma |
CA3201293A1 (en) | 2007-03-07 | 2008-09-12 | Abraxis Bioscience, Llc | Nanoparticle comprising rapamycin and albumin as anticancer agent |
CN101053553B (en) | 2007-03-16 | 2011-04-20 | 吉林大学 | Biodegradable fluorourcacil polyester medicine-carried nanospheres and its preparation method |
WO2008124634A1 (en) | 2007-04-04 | 2008-10-16 | Massachusetts Institute Of Technology | Polymer-encapsulated reverse micelles |
CN101678113B (en) | 2007-05-14 | 2012-05-30 | 日本株式会社Ltt生物医药 | Low-molecule drug-containing nanoparticle having sustained release negatively charged group |
US9422234B2 (en) | 2007-11-30 | 2016-08-23 | The Johns Hopkins University | Prostate specific membrane antigen (PSMA) targeted nanoparticles for therapy of prostate cancer |
DE102007059752A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Functionalized solid polymer nanoparticles containing epothilones |
WO2009084801A1 (en) | 2007-12-31 | 2009-07-09 | Samyang Corporation | Amphiphilic block copolymer micelle composition containing taxane and manufacturing process of the same |
EP2106806A1 (en) | 2008-03-31 | 2009-10-07 | Fraunhofer-Gesellschaft zur Förderung der Angewandten Forschung e.V. | Nanoparticles for targeted delivery of active agents to the lung |
US8613951B2 (en) * | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
EP2285350B1 (en) | 2008-06-16 | 2017-11-15 | Pfizer Inc | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic nanoparticles |
WO2010114770A1 (en) | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
EA201171195A8 (en) | 2009-03-30 | 2014-08-29 | Серулин Фарма Инк. | CONJUGATES, PARTICLES, POLYMER-AGENT COMPOSITIONS AND METHODS OF THEIR APPLICATION |
WO2010114768A1 (en) | 2009-03-30 | 2010-10-07 | Cerulean Pharma Inc. | Polymer-epothilone conjugates, particles, compositions, and related methods of use |
JP5442746B2 (en) | 2009-10-01 | 2014-03-12 | 三洋電機株式会社 | Image display device |
WO2011084518A2 (en) * | 2009-12-15 | 2011-07-14 | Bind Biosciences, Inc. | Therapeutic polymeric nanoparticles comprising corticosteroids and methods of making and using same |
JP5898627B2 (en) * | 2009-12-15 | 2016-04-06 | バインド セラピューティックス インコーポレイテッド | Therapeutic polymer nanoparticles containing epothilone and methods of making and using the same |
EP2515946B1 (en) | 2009-12-23 | 2019-05-22 | The Board of Trustees of the University of Illionis | Nanoconjugates and nanoconjugate formulations |
WO2011119995A2 (en) | 2010-03-26 | 2011-09-29 | Cerulean Pharma Inc. | Formulations and methods of use |
EP2395259B1 (en) * | 2010-06-11 | 2012-11-07 | iwis motorsysteme GmbH & Co. KG | Tensioning device with stop bracket |
WO2012040513A1 (en) | 2010-09-22 | 2012-03-29 | The Board Of Regents Of The University Of Texas System | Compositions and methods for the delivery of beta lapachone |
WO2012054923A2 (en) | 2010-10-22 | 2012-04-26 | Bind Biosciences, Inc. | Therapeutic nanoparticles with high molecular weight copolymers |
WO2012166923A2 (en) | 2011-05-31 | 2012-12-06 | Bind Biosciences | Drug loaded polymeric nanoparticles and methods of making and using same |
US20150017245A1 (en) | 2011-09-22 | 2015-01-15 | Bind Therapeutics, Inc. | Methods of treating cancers with therapeutic nanoparticles |
CA2865700C (en) | 2012-02-29 | 2020-05-05 | Merck Patent Gmbh | Process for the production of nanoparticles laden with active compound |
JP6356678B2 (en) | 2012-09-17 | 2018-07-11 | ファイザー・インク | Method for producing therapeutic nanoparticles |
AU2013315125B2 (en) | 2012-09-17 | 2018-07-26 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using same |
MX2016000131A (en) | 2013-06-28 | 2016-06-15 | Bind Therapeutics Inc | Docetaxel polymeric nanoparticles for cancer treatment. |
-
2009
- 2009-12-15 EA EA201100765A patent/EA201100765A1/en unknown
- 2009-12-15 ES ES09835578T patent/ES2776126T3/en active Active
- 2009-12-15 WO PCT/US2009/068028 patent/WO2010075072A2/en active Application Filing
- 2009-12-15 JP JP2011540968A patent/JP2012512175A/en active Pending
- 2009-12-15 US US12/638,297 patent/US20100216804A1/en not_active Abandoned
- 2009-12-15 EP EP09835578.7A patent/EP2379064B1/en active Active
-
2011
- 2011-05-16 US US13/108,361 patent/US20110217377A1/en not_active Abandoned
-
2012
- 2012-07-24 US US13/556,647 patent/US9308179B2/en active Active
-
2013
- 2013-12-09 US US14/100,695 patent/US9198874B2/en active Active
-
2015
- 2015-04-23 JP JP2015088181A patent/JP2015143268A/en not_active Withdrawn
- 2015-10-26 US US14/922,755 patent/US20160045608A1/en not_active Abandoned
-
2017
- 2017-06-28 JP JP2017125985A patent/JP2017165780A/en not_active Withdrawn
-
2019
- 2019-04-22 JP JP2019081186A patent/JP2019142924A/en active Pending
Patent Citations (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5766635A (en) * | 1991-06-28 | 1998-06-16 | Rhone-Poulenc Rorer S.A. | Process for preparing nanoparticles |
US5578325A (en) * | 1993-07-23 | 1996-11-26 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
US6007845A (en) * | 1994-07-22 | 1999-12-28 | Massachusetts Institute Of Technology | Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers |
US6346274B1 (en) * | 1995-03-10 | 2002-02-12 | Roche Diagnostics Gmbh | Polypeptide-containing pharmaceutical forms of administration in the form of microparticles and method for the preparation thereof |
US6902743B1 (en) * | 1995-05-22 | 2005-06-07 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive material(s) encapuslated within a biodegradable-bio-compatable polymeric matrix |
US7422902B1 (en) * | 1995-06-07 | 2008-09-09 | The University Of British Columbia | Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer |
US6139870A (en) * | 1995-12-19 | 2000-10-31 | Aventis Pharma Sa | Stabilized nanoparticles which are filterable under sterile conditions |
US20010008998A1 (en) * | 1996-05-15 | 2001-07-19 | Masato Tamaki | Business processing system employing a notice board business system database and method of processing the same |
US6254890B1 (en) * | 1997-12-12 | 2001-07-03 | Massachusetts Institute Of Technology | Sub-100nm biodegradable polymer spheres capable of transporting and releasing nucleic acids |
US20020045582A1 (en) * | 1997-12-31 | 2002-04-18 | Alexey L. Margolin | Stabilized protein crystals formulations containing them and methods of making them |
US6395718B1 (en) * | 1998-07-06 | 2002-05-28 | Guilford Pharmaceuticals Inc. | Pharmaceutical compositions and methods of inhibiting angiogenesis using naaladase inhibitors |
US6265609B1 (en) * | 1998-07-06 | 2001-07-24 | Guilford Pharmaceuticals Inc. | Thio-substituted pentanedioic acid derivatives |
US20040071768A1 (en) * | 1999-04-01 | 2004-04-15 | Inex Pharmaceuticals Corporation | Compositions and methods for treating cancer |
US20040086544A1 (en) * | 1999-09-30 | 2004-05-06 | Chienna B.V. | Polymers with bioactive agents |
US20050037086A1 (en) * | 1999-11-19 | 2005-02-17 | Zycos Inc., A Delaware Corporation | Continuous-flow method for preparing microparticles |
US6528499B1 (en) * | 2000-04-27 | 2003-03-04 | Georgetown University | Ligands for metabotropic glutamate receptors and inhibitors of NAALADase |
US20030143184A1 (en) * | 2000-05-17 | 2003-07-31 | Min-Hyo Seo | Stable polymeric micelle-type drug composition and method for the preparation thereof |
US20020119916A1 (en) * | 2000-12-22 | 2002-08-29 | Hassan Emadeldin M. | Elemental nanoparticles of substantially water insoluble materials |
US6875886B2 (en) * | 2001-02-07 | 2005-04-05 | Beth Israel Deaconess Medical Center, Inc. | Modified PSMA ligands and uses related thereto |
US20040219224A1 (en) * | 2001-06-21 | 2004-11-04 | Kirill Yakovlevsky | Spherical protein particles and methods for making and using them |
US20060110460A1 (en) * | 2001-10-10 | 2006-05-25 | Eulalia Ferret | Prolonged release biodegradable microspheres and method for preparing same |
US20030235619A1 (en) * | 2001-12-21 | 2003-12-25 | Christine Allen | Polymer-lipid delivery vehicles |
US20040054190A1 (en) * | 2002-01-10 | 2004-03-18 | Johns Hopkins University | Imaging agents and methods of imaging NAALADase or PSMA |
US20060165987A1 (en) * | 2002-04-05 | 2006-07-27 | Patrice Hildgen | Stealthy polymeric biodegradable nanospheres and uses thereof |
US20030232887A1 (en) * | 2002-04-10 | 2003-12-18 | Johnson Douglas Giles | Preparation and use of a stable formulation of allosteric effector compounds |
US6890950B2 (en) * | 2002-04-23 | 2005-05-10 | Case Western Reserve University | Lapachone delivery systems, compositions and uses related thereto |
US20060057219A1 (en) * | 2002-05-24 | 2006-03-16 | Nanocarrier Co., Ltd. | Method for preparing a polymer micelle pharmaceutical preparation containing drug for injection |
US20070041901A1 (en) * | 2002-06-18 | 2007-02-22 | Diener John L | Stabilized aptamers to PSMA and their use as prostate cancer therapeutics |
US20110159079A1 (en) * | 2002-10-29 | 2011-06-30 | Zhili Li | High Delivery Rates for Lipid Based Drug Formulations, and Methods of Treatment Thereof |
US20040220081A1 (en) * | 2002-10-30 | 2004-11-04 | Spherics, Inc. | Nanoparticulate bioactive agents |
US6841547B2 (en) * | 2003-02-28 | 2005-01-11 | Albert Einstein College Of Medicine Of Yeshevia University | Method for decreasing low density lipoprotein |
US20040185170A1 (en) * | 2003-03-21 | 2004-09-23 | Shubha Chungi | Method for coating drug-containing particles and formulations and dosage units formed therefrom |
WO2004084871A1 (en) * | 2003-03-26 | 2004-10-07 | Ltt Bio-Pharma Co., Ltd. | Intravenous nanoparticles for targenting drug delivery and sustained drug release |
US20040247624A1 (en) * | 2003-06-05 | 2004-12-09 | Unger Evan Charles | Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility |
US20050037075A1 (en) * | 2003-06-06 | 2005-02-17 | Farokhzad Omid C. | Targeted delivery of controlled release polymer systems |
US20040247680A1 (en) * | 2003-06-06 | 2004-12-09 | Farokhzad Omid C. | Targeted delivery of controlled release polymer systems |
US20050256071A1 (en) * | 2003-07-15 | 2005-11-17 | California Institute Of Technology | Inhibitor nucleic acids |
US20050142205A1 (en) * | 2003-07-18 | 2005-06-30 | Julia Rashba-Step | Methods for encapsulating small spherical particles prepared by controlled phase separation |
US20050136258A1 (en) * | 2003-12-22 | 2005-06-23 | Shuming Nie | Bioconjugated nanostructures, methods of fabrication thereof, and methods of use thereof |
US20070053845A1 (en) * | 2004-03-02 | 2007-03-08 | Shiladitya Sengupta | Nanocell drug delivery system |
US20050266067A1 (en) * | 2004-03-02 | 2005-12-01 | Shiladitya Sengupta | Nanocell drug delivery system |
US20080124400A1 (en) * | 2004-06-24 | 2008-05-29 | Angiotech International Ag | Microparticles With High Loadings Of A Bioactive Agent |
US20060002852A1 (en) * | 2004-07-01 | 2006-01-05 | Yale University | Targeted and high density drug loaded polymeric materials |
US20060002971A1 (en) * | 2004-07-01 | 2006-01-05 | Yale University | Methods of treatment with drug loaded polymeric materials |
US20090074753A1 (en) * | 2004-10-14 | 2009-03-19 | Lynch Samuel E | Platelet-derived growth factor compositions and methods of use thereof |
US20070043066A1 (en) * | 2005-07-11 | 2007-02-22 | Wyeth | Glutamate aggrecanase inhibitors |
US20070031402A1 (en) * | 2005-08-03 | 2007-02-08 | Immunogen Inc. | Immunoconjugate formulations |
US8034765B2 (en) * | 2005-08-31 | 2011-10-11 | Abraxis Bioscience, Llc | Compositions and methods for preparation of poorly water soluble drugs with increased stability |
US20090053293A1 (en) * | 2005-09-09 | 2009-02-26 | Beijing Diacrid Medical Technology Co., Ltd. | Nano Anticancer Micelles of Vinca Alkaloids Entrapped in Polyethylene Glycolylated Phospholipids |
US20090317479A1 (en) * | 2005-12-26 | 2009-12-24 | Tsutomu Ishihara | Nanoparticles containing water-soluble non-peptide low-molecular weight drug |
US20070154554A1 (en) * | 2005-12-29 | 2007-07-05 | Robert Burgermeister | Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same |
US20090155349A1 (en) * | 2006-02-23 | 2009-06-18 | Jonathan Daniel Heller | Methods of treating influenza viral infections |
US20080081074A1 (en) * | 2006-05-15 | 2008-04-03 | Massachusetts Institute Of Technology | Polymers for functional particles |
US20090170753A1 (en) * | 2006-07-26 | 2009-07-02 | Christian Welz | Capsofungin formulations |
US20080057102A1 (en) * | 2006-08-21 | 2008-03-06 | Wouter Roorda | Methods of manufacturing medical devices for controlled drug release |
US20080193381A1 (en) * | 2006-11-08 | 2008-08-14 | Molecular Insight Pharmaceuticals, Inc. | Heterodimers of glutamic acid |
US20090061010A1 (en) * | 2007-03-30 | 2009-03-05 | Massachusetts Institute Of Technology | Cancer cell targeting using nanoparticles |
US20090074828A1 (en) * | 2007-04-04 | 2009-03-19 | Massachusetts Institute Of Technology | Poly(amino acid) targeting moieties |
US20090053315A1 (en) * | 2007-08-21 | 2009-02-26 | Board Of Regents, The University Of Texas System | Thermo-Kinetic Mixing for Pharmaceutical Applications |
US20090061009A1 (en) * | 2007-08-29 | 2009-03-05 | Joseph Schwarz | Composition and Method of Treatment of Bacterial Infections |
US20120004293A1 (en) * | 2007-09-28 | 2012-01-05 | Zale Stephen E | Cancer Cell Targeting Using Nanoparticles |
US20110224288A1 (en) * | 2007-09-28 | 2011-09-15 | Zale Stephen E | Cancer Cell Targeting Using Nanoparticles |
US20090306120A1 (en) * | 2007-10-23 | 2009-12-10 | Florencia Lim | Terpolymers containing lactide and glycolide |
US20100068286A1 (en) * | 2008-06-16 | 2010-03-18 | Greg Troiano | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100104655A1 (en) * | 2008-06-16 | 2010-04-29 | Zale Stephen E | Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same |
US20100068285A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20110274759A1 (en) * | 2008-06-16 | 2011-11-10 | Greg Troiano | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100040537A1 (en) * | 2008-07-08 | 2010-02-18 | Abbott Laboratories | Prostaglandin E2 Binding Proteins and Uses Thereof |
US20100087337A1 (en) * | 2008-09-10 | 2010-04-08 | Bind Biosciences, Inc. | High Throughput Fabrication of Nanoparticles |
US20100226986A1 (en) * | 2008-12-12 | 2010-09-09 | Amy Grayson | Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same |
US20110217377A1 (en) * | 2008-12-15 | 2011-09-08 | Zale Stephen E | Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents |
US20100316725A1 (en) * | 2009-05-27 | 2010-12-16 | Elan Pharma International Ltd. | Reduction of flake-like aggregation in nanoparticulate active agent compositions |
US20110275704A1 (en) * | 2009-12-11 | 2011-11-10 | Greg Troiano | Stable Formulations for Lyophilizing Therapeutic Particles |
US20120027820A1 (en) * | 2009-12-11 | 2012-02-02 | Greg Troiano | Stable Formulations for Lyophilizing Therapeutic Particles |
US20110294717A1 (en) * | 2009-12-15 | 2011-12-01 | Ali Mir M | Therapeutic Polymeric Nanoparticle Compositions with High Glass Transition Temperature or High Molecular Weight Copolymers |
Cited By (163)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9492400B2 (en) | 2004-11-04 | 2016-11-15 | Massachusetts Institute Of Technology | Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals |
US9267937B2 (en) | 2005-12-15 | 2016-02-23 | Massachusetts Institute Of Technology | System for screening particles |
US8709483B2 (en) | 2006-03-31 | 2014-04-29 | Massachusetts Institute Of Technology | System for targeted delivery of therapeutic agents |
US8802153B2 (en) | 2006-03-31 | 2014-08-12 | Massachusetts Institute Of Technology | System for targeted delivery of therapeutic agents |
US9381477B2 (en) | 2006-06-23 | 2016-07-05 | Massachusetts Institute Of Technology | Microfluidic synthesis of organic nanoparticles |
US9217129B2 (en) | 2007-02-09 | 2015-12-22 | Massachusetts Institute Of Technology | Oscillating cell culture bioreactor |
US20090061010A1 (en) * | 2007-03-30 | 2009-03-05 | Massachusetts Institute Of Technology | Cancer cell targeting using nanoparticles |
US8246968B2 (en) | 2007-03-30 | 2012-08-21 | Bind Biosciences, Inc. | Cancer cell targeting using nanoparticles |
US9333179B2 (en) | 2007-04-04 | 2016-05-10 | Massachusetts Institute Of Technology | Amphiphilic compound assisted nanoparticles for targeted delivery |
US9295727B2 (en) | 2007-09-28 | 2016-03-29 | Bind Therapeutics, Inc. | Cancer cell targeting using nanoparticles |
US10071056B2 (en) | 2007-09-28 | 2018-09-11 | Pfizer Inc. | Cancer cell targeting using nanoparticles |
US10736848B2 (en) | 2007-10-12 | 2020-08-11 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US11547667B2 (en) | 2007-10-12 | 2023-01-10 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US9539210B2 (en) | 2007-10-12 | 2017-01-10 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US9474717B2 (en) | 2007-10-12 | 2016-10-25 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US9526702B2 (en) | 2007-10-12 | 2016-12-27 | Massachusetts Institute Of Technology | Vaccine nanotechnology |
US8293276B2 (en) | 2008-06-16 | 2012-10-23 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8663700B2 (en) | 2008-06-16 | 2014-03-04 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9351933B2 (en) | 2008-06-16 | 2016-05-31 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same |
US20100068286A1 (en) * | 2008-06-16 | 2010-03-18 | Greg Troiano | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US9579386B2 (en) | 2008-06-16 | 2017-02-28 | Pfizer Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8603534B2 (en) | 2008-06-16 | 2013-12-10 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8609142B2 (en) | 2008-06-16 | 2013-12-17 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8613951B2 (en) | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US8613954B2 (en) | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8617608B2 (en) | 2008-06-16 | 2013-12-31 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8623417B1 (en) | 2008-06-16 | 2014-01-07 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same |
US8420123B2 (en) | 2008-06-16 | 2013-04-16 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8652528B2 (en) | 2008-06-16 | 2014-02-18 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9375481B2 (en) | 2008-06-16 | 2016-06-28 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9393310B2 (en) | 2008-06-16 | 2016-07-19 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9579284B2 (en) | 2008-06-16 | 2017-02-28 | Pfizer Inc. | Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same |
US8318208B1 (en) | 2008-06-16 | 2012-11-27 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8318211B2 (en) | 2008-06-16 | 2012-11-27 | Bind Biosciences, Inc. | Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same |
US8206747B2 (en) | 2008-06-16 | 2012-06-26 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US20100069426A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US20100068285A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100104655A1 (en) * | 2008-06-16 | 2010-04-29 | Zale Stephen E | Therapeutic Polymeric Nanoparticles Comprising Vinca Alkaloids and Methods of Making and Using Same |
US8932595B2 (en) | 2008-10-12 | 2015-01-13 | Massachusetts Institute Of Technology | Nicotine immunonanotherapeutics |
US8906381B2 (en) | 2008-10-12 | 2014-12-09 | Massachusetts Institute Of Technology | Immunonanotherapeutics that provide IGG humoral response without T-cell antigen |
US20100226986A1 (en) * | 2008-12-12 | 2010-09-09 | Amy Grayson | Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same |
US8905997B2 (en) | 2008-12-12 | 2014-12-09 | Bind Therapeutics, Inc. | Therapeutic particles suitable for parenteral administration and methods of making and using same |
US8563041B2 (en) | 2008-12-12 | 2013-10-22 | Bind Therapeutics, Inc. | Therapeutic particles suitable for parenteral administration and methods of making and using same |
US9198874B2 (en) | 2008-12-15 | 2015-12-01 | Bind Therapeutics, Inc. | Long circulating nanoparticles for sustained release of therapeutic agents |
US9308179B2 (en) | 2008-12-15 | 2016-04-12 | Bind Therapeutics, Inc. | Long circulating nanoparticles for sustained release of therapeutic agents |
US20110217377A1 (en) * | 2008-12-15 | 2011-09-08 | Zale Stephen E | Long Circulating Nanoparticles for Sustained Release of Therapeutic Agents |
US9872848B2 (en) | 2009-12-11 | 2018-01-23 | Pfizer Inc. | Stable formulations for lyophilizing therapeutic particles |
US8956657B2 (en) | 2009-12-11 | 2015-02-17 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US9498443B2 (en) | 2009-12-11 | 2016-11-22 | Pfizer Inc. | Stable formulations for lyophilizing therapeutic particles |
US8211473B2 (en) | 2009-12-11 | 2012-07-03 | Bind Biosciences, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8916203B2 (en) | 2009-12-11 | 2014-12-23 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8357401B2 (en) | 2009-12-11 | 2013-01-22 | Bind Biosciences, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8603535B2 (en) | 2009-12-11 | 2013-12-10 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8637083B2 (en) | 2009-12-11 | 2014-01-28 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US9835572B2 (en) | 2009-12-15 | 2017-12-05 | Pfizer Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US9295649B2 (en) | 2009-12-15 | 2016-03-29 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US8518963B2 (en) | 2009-12-15 | 2013-08-27 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US8912212B2 (en) | 2009-12-15 | 2014-12-16 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US20130059946A1 (en) * | 2011-04-25 | 2013-03-07 | Jingxu Zhu | Biocompatible polymer nanoparticle coating composition and method of production thereof |
US8987354B2 (en) * | 2011-04-25 | 2015-03-24 | Jingxu Zhu | Biocompatible polymer nanoparticle coating composition and method of production thereof |
EP4144378A1 (en) | 2011-12-16 | 2023-03-08 | ModernaTX, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
WO2013151736A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | In vivo production of proteins |
WO2013151666A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US10555911B2 (en) * | 2012-05-04 | 2020-02-11 | Yale University | Highly penetrative nanocarriers for treatment of CNS disease |
US20150118311A1 (en) * | 2012-05-04 | 2015-04-30 | Yale Universit | Highly Penetrative Nanocarriers for Treatment of CNS Disease |
US9314532B2 (en) | 2012-08-10 | 2016-04-19 | University Of North Texas Health Science Center | Drug delivery vehicle |
US9877923B2 (en) | 2012-09-17 | 2018-01-30 | Pfizer Inc. | Process for preparing therapeutic nanoparticles |
EP4074834A1 (en) | 2012-11-26 | 2022-10-19 | ModernaTX, Inc. | Terminally modified rna |
US9309114B2 (en) * | 2013-01-14 | 2016-04-12 | Xerox Corporation | Porous nanoparticles produced by solvent-free emulsification |
US20140199352A1 (en) * | 2013-01-14 | 2014-07-17 | Xerox Corporation | Porous nanoparticles produced by solvent-free emulsification |
US20160136607A1 (en) * | 2013-01-14 | 2016-05-19 | Xerox Corporation | Porous nanoparticles produced by solvent-free emulsification |
WO2014152211A1 (en) | 2013-03-14 | 2014-09-25 | Moderna Therapeutics, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
WO2014152540A1 (en) | 2013-03-15 | 2014-09-25 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10967039B2 (en) | 2013-05-28 | 2021-04-06 | Sintef Tto As | Process for preparing stealth nanoparticles |
EP3971287A1 (en) | 2013-07-11 | 2022-03-23 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
WO2015006747A2 (en) | 2013-07-11 | 2015-01-15 | Moderna Therapeutics, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use. |
WO2015034928A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
US20170138387A1 (en) * | 2013-11-22 | 2017-05-18 | Sannohashi Corporation | Bolt, nut, and strain measurement system |
WO2015075557A2 (en) | 2013-11-22 | 2015-05-28 | Mina Alpha Limited | C/ebp alpha compositions and methods of use |
EP3594348A1 (en) | 2013-11-22 | 2020-01-15 | Mina Therapeutics Limited | C/ebp alpha short activating rna compositions and methods of use |
EP3985118A1 (en) | 2013-11-22 | 2022-04-20 | MiNA Therapeutics Limited | C/ebp alpha short activating rna compositions and methods of use |
US9895378B2 (en) | 2014-03-14 | 2018-02-20 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same |
US10071100B2 (en) | 2014-03-14 | 2018-09-11 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same |
EP4159741A1 (en) | 2014-07-16 | 2023-04-05 | ModernaTX, Inc. | Method for producing a chimeric polynucleotide encoding a polypeptide having a triazole-containing internucleotide linkage |
WO2016014846A1 (en) | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of intrabodies |
WO2017070623A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Herpes simplex virus vaccine |
EP4011451A1 (en) | 2015-10-22 | 2022-06-15 | ModernaTX, Inc. | Metapneumovirus mrna vaccines |
WO2017070620A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Broad spectrum influenza virus vaccine |
WO2017070601A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Nucleic acid vaccines for varicella zoster virus (vzv) |
WO2017070613A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2017070622A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory syncytial virus vaccine |
WO2017070626A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory virus vaccines |
EP4039699A1 (en) | 2015-12-23 | 2022-08-10 | ModernaTX, Inc. | Methods of using ox40 ligand encoding polynucleotides |
WO2017112943A1 (en) | 2015-12-23 | 2017-06-29 | Modernatx, Inc. | Methods of using ox40 ligand encoding polynucleotides |
WO2017120612A1 (en) | 2016-01-10 | 2017-07-13 | Modernatx, Inc. | Therapeutic mrnas encoding anti ctla-4 antibodies |
US10548881B2 (en) | 2016-02-23 | 2020-02-04 | Tarveda Therapeutics, Inc. | HSP90 targeted conjugates and particles and formulations thereof |
US11510910B2 (en) | 2016-02-23 | 2022-11-29 | Tva (Abc), Llc | HSP90 targeted conjugates and particles and formulations thereof |
WO2018213731A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
WO2018213789A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Modified messenger rna comprising functional rna elements |
EP4253544A2 (en) | 2017-05-18 | 2023-10-04 | ModernaTX, Inc. | Modified messenger rna comprising functional rna elements |
WO2018232006A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
US20180369231A1 (en) * | 2017-06-22 | 2018-12-27 | SNBioScience Inc. | Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same |
US11793803B2 (en) | 2017-06-22 | 2023-10-24 | Sn Bioscience Inc. | Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same |
US11793804B2 (en) | 2017-06-22 | 2023-10-24 | Sn Bioscience Inc. | Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same |
WO2019048645A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
WO2019048631A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Hnf4a sarna compositions and methods of use |
WO2019048632A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
EP4183882A1 (en) | 2017-09-08 | 2023-05-24 | MiNA Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
EP4233880A2 (en) | 2017-09-08 | 2023-08-30 | MiNA Therapeutics Limited | Hnf4a sarna compositions and methods of use |
EP4219715A2 (en) | 2017-09-08 | 2023-08-02 | MiNA Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
WO2019104160A2 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
WO2019104152A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
WO2019104195A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia |
WO2019136241A1 (en) | 2018-01-05 | 2019-07-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
US20200405642A1 (en) * | 2018-02-26 | 2020-12-31 | AnTolRx, Inc. | Tolerogenic liposomes and methods of use thereof |
WO2019200171A1 (en) | 2018-04-11 | 2019-10-17 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
EP4242307A2 (en) | 2018-04-12 | 2023-09-13 | MiNA Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2019197845A1 (en) | 2018-04-12 | 2019-10-17 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
US11802296B2 (en) | 2018-05-16 | 2023-10-31 | Synthego Corporation | Methods and systems for guide RNA design and use |
US11697827B2 (en) | 2018-05-16 | 2023-07-11 | Synthego Corporation | Systems and methods for gene modification |
US11345932B2 (en) | 2018-05-16 | 2022-05-31 | Synthego Corporation | Methods and systems for guide RNA design and use |
WO2019226650A1 (en) | 2018-05-23 | 2019-11-28 | Modernatx, Inc. | Delivery of dna |
WO2020023390A1 (en) | 2018-07-25 | 2020-01-30 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
WO2020047201A1 (en) | 2018-09-02 | 2020-03-05 | Modernatx, Inc. | Polynucleotides encoding very long-chain acyl-coa dehydrogenase for the treatment of very long-chain acyl-coa dehydrogenase deficiency |
WO2020056155A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease |
WO2020056147A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding glucose-6-phosphatase for the treatment of glycogen storage disease |
WO2020056239A1 (en) | 2018-09-14 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2020069169A1 (en) | 2018-09-27 | 2020-04-02 | Modernatx, Inc. | Polynucleotides encoding arginase 1 for the treatment of arginase deficiency |
WO2020097409A2 (en) | 2018-11-08 | 2020-05-14 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
US11884918B2 (en) | 2019-01-25 | 2024-01-30 | Synthego Corporation | Systems and methods for modulating CRISPR activity |
WO2020208361A1 (en) | 2019-04-12 | 2020-10-15 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2020227642A1 (en) | 2019-05-08 | 2020-11-12 | Modernatx, Inc. | Compositions for skin and wounds and methods of use thereof |
WO2020263985A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Messenger rna comprising functional rna elements and uses thereof |
WO2020263883A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Endonuclease-resistant messenger rna and uses thereof |
WO2021061707A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | Compositions and methods for modulating apolipoprotein b (apob) gene expression |
WO2021061815A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR MODULATING HEPATOCYTE NUCLEAR FACTOR 4-ALPHA (HNF4α) GENE EXPRESSION |
WO2021183720A1 (en) | 2020-03-11 | 2021-09-16 | Omega Therapeutics, Inc. | Compositions and methods for modulating forkhead box p3 (foxp3) gene expression |
WO2021247507A1 (en) | 2020-06-01 | 2021-12-09 | Modernatx, Inc. | Phenylalanine hydroxylase variants and uses thereof |
WO2021252354A1 (en) | 2020-06-12 | 2021-12-16 | University Of Rochester | ENCODING AND EXPRESSION OF ACE-tRNAs |
WO2022104131A1 (en) | 2020-11-13 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
WO2022122872A1 (en) | 2020-12-09 | 2022-06-16 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2022204380A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof |
WO2022204369A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia |
WO2022204390A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof |
WO2022204370A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency |
WO2022204371A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof |
WO2022200810A1 (en) | 2021-03-26 | 2022-09-29 | Mina Therapeutics Limited | Tmem173 sarna compositions and methods of use |
WO2022240806A1 (en) | 2021-05-11 | 2022-11-17 | Modernatx, Inc. | Non-viral delivery of dna for prolonged polypeptide expression in vivo |
WO2022266083A2 (en) | 2021-06-15 | 2022-12-22 | Modernatx, Inc. | Engineered polynucleotides for cell-type or microenvironment-specific expression |
WO2022271776A1 (en) | 2021-06-22 | 2022-12-29 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2023283359A2 (en) | 2021-07-07 | 2023-01-12 | Omega Therapeutics, Inc. | Compositions and methods for modulating secreted frizzled receptor protein 1 (sfrp1) gene expression |
WO2023055998A3 (en) * | 2021-09-30 | 2023-09-14 | The Trustees Of Princeton University | Dna valency sorting chromatography |
WO2023056044A1 (en) | 2021-10-01 | 2023-04-06 | Modernatx, Inc. | Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023104964A1 (en) | 2021-12-09 | 2023-06-15 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2023150753A1 (en) | 2022-02-07 | 2023-08-10 | University Of Rochester | Optimized sequences for enhanced trna expression or/and nonsense mutation suppression |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023183909A2 (en) | 2022-03-25 | 2023-09-28 | Modernatx, Inc. | Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia |
WO2023196399A1 (en) | 2022-04-06 | 2023-10-12 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding argininosuccinate lyase for the treatment of argininosuccinic aciduria |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
WO2024026254A1 (en) | 2022-07-26 | 2024-02-01 | Modernatx, Inc. | Engineered polynucleotides for temporal control of expression |
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WO2010075072A2 (en) | 2010-07-01 |
EA201100765A1 (en) | 2012-04-30 |
WO2010075072A3 (en) | 2010-10-14 |
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JP2019142924A (en) | 2019-08-29 |
US20110217377A1 (en) | 2011-09-08 |
JP2012512175A (en) | 2012-05-31 |
US20140093579A1 (en) | 2014-04-03 |
US20130034608A1 (en) | 2013-02-07 |
JP2017165780A (en) | 2017-09-21 |
EP2379064A4 (en) | 2012-06-20 |
US9198874B2 (en) | 2015-12-01 |
US9308179B2 (en) | 2016-04-12 |
ES2776126T3 (en) | 2020-07-29 |
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