CN1224622A - Tumor target direction contrast agent - Google Patents
Tumor target direction contrast agent Download PDFInfo
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- CN1224622A CN1224622A CN 98110637 CN98110637A CN1224622A CN 1224622 A CN1224622 A CN 1224622A CN 98110637 CN98110637 CN 98110637 CN 98110637 A CN98110637 A CN 98110637A CN 1224622 A CN1224622 A CN 1224622A
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Abstract
The tumor targeted contrast medium is binary crosslinked product by crosslinking chemically available CT or MRI contrast medium (diatrizoate meglumine, ultravist or iopamidol, etc.) with tumor affine matter, such as sulfadiazine and tetracycline, or antineoplastic membrane protein monoclone antibody, or growth factor receptor monoclone antibody. It may also be ternary crosslinked product by crosslinking chemically available CT or MRI contrast medium with tumor affine matter through human serum albumin. The contrast medium of the present invention has the feature of focusing in the part of tumor tissue and thus increasing the density of tumor focus, so that it can raise the specificity and sensitivity of CT and MRI scan in tumor diagnosis.
Description
The present invention relates to the imaging diagnosis medicine,, be used for the diagnosis of computer-tomography (CT) and nuclear magnetic resonance (MRI) enhanced ct scans tumor especially about a kind of tumor target direction contrast agent.
Contrast agent is meant that specific part is introduced certain high density or materials of low density in body in the contrast examination of X line, thereby produces the difference on the density, and relevant structure or organ are developed, and this class material is called contrast agent.In the clinical practice, when a certain structure or intraorganic unusual focus are carried out computer-tomography or MRI scan and are checked in to body, in order to increase the density of unusual focus, improve the resolution of CT and MRI scanning to lesion tissue, must carry out enhanced ct scans from the intravenous contrast agent, for example at present clinically the CT enhanced ct scans with cardiografin or Omnipaque, MRI enhanced ct scans DTPA-Gd meglumine.Yet because these phlebography agent shortages commonly used and the affinity of tumor tissues, though CT and MRI enhanced ct scans can be by abundant tumor blood for the density that increases tumor focus, degree is limited, and tumor focus is also lacked specificity.Therefore, CT and MRI scanning still lacks parameter index very reliably aspect diagnosing tumor.In addition, nationality parent tumor material adopts the radionuclide image diagnosing tumour, but has isotopic contamination and the lower shortcoming of visualization resolution, and most of hospital does not have this special picture reproducer.
For this reason, the object of the invention provides a kind of tumor target direction contrast agent, and it is the phlebography agent with tumor tissues guide function, is used for CT and MRI enhanced ct scans, improves the resolution of CT and MRI scanning to tumor focus.
The present invention is a kind of tumor target direction contrast agent, it is to be connected into binary cross-linking agent with phlebography agent and close tumor material by chemical crosslink technique by CT or MRI enhanced ct scans, or be connected into the ternary cross-linking agent with phlebography agent, close tumor material and human serum albumin by chemical crosslink technique by CT or MRI enhanced ct scans, be contrast agent with tumor targeting characteristic.In the time that this contrast agent is quite lacked after intravenous injection, can combine with the tumor tissues specificity, the result significantly improves the density of tumor tissues intralesional when CT and MRI scanning, and enhanced CT and MRI scanning are to the specificity and the sensitivity of diagnosing tumor.The present invention adopts following close tumor material: 1. sulfadiazine chemical compound
Sulfadiazine is at first reported (Stevens CD, Quinlin PM, Meinken MA, et al.Science 112:561 in the fifties by Stevens in the selective aggregation phenomenon of tumor tissues focus; 1950).Calvert etc. further confirms close tumor characteristic (Calvert N, Conors TA, RossWCJ, the et al.Eur J Cancer 4:627 of sulfa drugs in the sixties; 1968).Because the sulfanilamide molecular weight is little, dissolubility height in contrast agent, and kinds of tumors tissue had affinity, therefore be the desirable oriented carrier for preparing tumor target direction contrast agent.2. tetracycline compound
Applied chemistry cross-linking method of the present invention labelling radionuclide on tetracycline
[1]In is used for the isotope video picture of lotus people pulmonary carcinoma nude mice model, and γ photograph result shows that tumor locus presents tangible radioactivity and assembles after 2 hours, has confirmed that tetracycline also has close tumor characteristic.The present invention also further confirms this close tumor characteristic of tetracycline on the kinds of tumors model.Tetracycline does not still have report both at home and abroad so far to the guidance quality clustering phenomena of tumor tissues.3. antitumor memebrane protein or growth factor receptors class monoclonal antibody
Studies confirm that in a large number antitumor memebrane protein monoclonal antibody and growth factor receptors class monoclonal antibody can be used as the carrier of tumor targeting therapy both at home and abroad, memebrane protein monoclonal antibodies such as for example anti-pulmonary carcinoma, hepatocarcinoma, breast carcinoma, glioma, ovarian cancer, squamous cell carcinoma and anti-epidermal growth factor receptor, neoplasm growth factor acceptor monoclonal antibody (Mehren MV and Weiner LM, Current Opinion in Oncology 8:493-498,1996) .The approval of existing polytype monoclonal antibody (comprising Mus source property monoclonal antibody) is gone on the market or is entered clinical trial both at home and abroad up to now.Especially the tumor growth factor receptor is expressed at the kinds of tumor cells height, and its monoclonal antibody can be used for the targeted therapy of kinds of tumors.CT or MRI strengthen scanning to be had a variety of with contrast preparation clinically; The present invention uses following contrast preparation: (1) cardiografin (mixed by amidotrizoic acid and meglumine, CT strengthen scanning with) preparation method 1. of (2) Omnipaque (CT strengthen scanning with) (3) Ultravist (CT strengthen scanning with) (4) iopamidol (CT strengthen scanning with) (5) DTPA-Gd meglumine (MRI strengthen scanning with) tumor target direction contrast agent of the present invention strengthens scanning by CT or MRI and connects by chemical crosslink technique with close tumour material with the phlebography agent and form phlebography agent-close tumour material binary cross-linking agent. Be example with amidotrizoic acid and sulfadiazine reaction below, the preparation AD-SD.
Based on amidotrizoic acid (Acidum Diatrizoicum, AD, FW=649.95) and sulfadiazine (molecular structure characteristics FW=250.28) (its molecular structure is as shown below) prepare by amidation process for Sulfadiazinum, SD.
Method A: list of references (Hurwitz E.et al, Cancer Res., 35:1175,1975; Carrsson J.et al, Biochem.J.173:723,1978) employing dicyclohexylcarbodiimide (DCC) evaporation
(dicyclohexylcarbodiimide FW=206) is a good acidylate condensing agent to DCC, and DCC at first generates the chemical compound with big acidylate ability with the carboxyl effect, and then generates amide with the amino effect.The present invention is dissolved in amidotrizoic acid and DCC in DMF or the DMSO equal solvent earlier, behind the reaction certain hour, sulfadiazine is added under the room temperature again, and reaction makes AD-SD between 0-37 ℃.Method B: list of references (Smith M.J.et al, J Natl.CancerInst., 76:503,1986; Kanello J.etal, J Natl.CancerInst., 75:319,1985) the employing active ester method
At first carboxylic acid and N-hydroxy-succinamide (are called for short NHS, FW=113) reaction generates the N-hydroxy-succinamide carboxylate under the DCC effect, and the reactivity of this ester and amine (ammonia) is very high, can react with it very soon to generate corresponding amide, and reaction condition is very gentle, and productive rate is also very high.The present invention is first to be dissolved in amidotrizoic acid and DCC in DMF or the DMSO equal solvent, and behind 37 ℃ of following reaction certain hours, the pyridine solution with NHS adds again, in 0-37 ℃ of following stirring reaction certain hour.Gained active ester derivative solution is in-20 ℃ of storages.At 0-37 ℃ of following stirring reaction certain hour, products therefrom promptly gets AD-SD by the chromatographic column separation and purification with gained active ester derivative and amine (or ammonia).2. the phlebography agent of being used by CT or MRI enhanced ct scans, close tumor material and human serum albumin are connected into phlebography agent-human serum albumin-close tumor material ternary cross-linking agent by chemical crosslink technique.Be that example prepares amidotrizoic acid-human serum albumin (HSA)-sulfadiazine ternary cross-linking agent with amidotrizoic acid, sulfadiazine and human serum albumin below.
Amidotrizoic acid-human serum albumin-sulfadiazine ternary cross-linking agent can make a part SD connect many AD molecules (5-30AD/SD) by intermediate HSA, thereby improves the aggregate amount of contrast agent at tumor locus.Molecular structure characteristics based on AD, SD and HSA (containing many amino in the molecule); at first on the SD molecule, introduce dimaleoyl imino or iodoacetyl; on the HSA molecule, introduce sulfydryl again; thereby the radical reaction of introducing in the sulfydryl of HSA molecule and the SD molecule makes SD and HSA crosslinked; and amino freely can the reaction in the HSA molecule, thereby make the purpose product with carboxyl or its activate ester derivative of AD.Introduce dimaleoyl imino or iodoacetyl, list of references (Kitagawa T.et al, JBiochem, 83:1493,1978 on the preparation method a.SD molecule; Camett M.C.et al, Jut.J.Cancer, 31:661,1983)
Iodoacetic acid N-hydroxy-succinamide ester (NSIA) is the Acibenzolar that is made by the reaction of iodoacetic acid and N-hydroxy-succinamide ester (NHS), and it reacts with amino in the SD molecule and introduce iodoacetyl on the SD molecule; M-maleimide yl benzoic acid N-hydroxy-succinamide ester (MBA) or 4-(N-maleimide) butanoic acid N-hydroxy-succinamide ester is respectively the Acibenzolar that is made by corresponding acid and NHS reaction, and the amino in this ester and the SD molecule reacts and introduce dimaleoyl imino on the SD molecule.Generally be to be solvent with DMF, ester used in the reactant is suitable with amino molal quantity, and reaction condition is relatively gentleer, and the about 0.5-2h of reaction gets final product product chromatographic column separation and purification under the room temperature.Introduce 2-pyridine disulfide group (DTP), list of references (Kitagawa T., Fujitake T.AndAikawa T.J.Biochem, 83:1493,1978) in the b.HSA molecule
3-(2-pyridine disulfide group) propanoic acid N-hydroxy-succinamide ester (SPDP) is dissolved in the ethanol, and the alcoholic solution with 5 times of excessive SPDP adds in the phosphate buffered solution (PBS) of HSA then, after reacting under the room temperature, by PD-10 post desalination cessation reaction.The molal quantity of the 2-pyridine disulfide group (DTP) in the HSA molecule can be measured with the following method, product is reduced with dithiothreitol, DTT (DTT), about 10min of response time, the final concentration of DTT is 50mM, measure DTP group or HSA 343 and the absworption peak at 280nm place, the molar extinction coefficient of DTP and HSA is respectively 8080 and 5100, calculates the DTP molal quantity of introducing in the HSA molecule.C.AD and HSA's is crosslinked, list of references (Juc R., Lombert J.M.and Traut R.R.Biochem, 1:5399,1978)
Add 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide (ECDI) in the NaOH aqueous solution of AD, behind the stirring reaction, add the PBS solution of HSA-DTP, AD: ECDI: the HSA mol ratio is 70: 100: 1.After the reaction, get AD-NH-HSA-SH under the room temperature by the chromatographic column separation and purification.D. amidotrizoic acid-human serum albumin (HSA)-sulfadiazine ternary cross-linking agent preparation, list of references (UmemotoN, Kato Y and Takahashi T.J Appl Biochem, 6:297,1984)
AD-HSA-DTP dithiothreitol, DTT (DTT) reduction, the final concentration of DTT is 50mM, then by the desalination of G-25 post, through outgasing, inflated with nitrogen was with the phosphate buffer balance of pH=7.2 before the G-25 post used.By the effusive solution of pillar directly with the SD molecular reaction of having introduced dimaleoyl imino or iodoacetyl, compound of reaction is after concentrating, stirring reaction spends the night under the room temperature, crude product gel permeation chromatography separation and purification must AD-HSA-SD ternary cross-linking agent.3. the preparation process of amidotrizoic acid-human serum albumin (HSA)-antitumor or growth factor receptors monoclonal antibody cross-linking agent and preparation that method is analogous to AD-HSA-SD.4. the preparation of DTPA-Gd meglumine targeted contrast agent and Omnipaque, Ultravist, iopamidol targeted contrast agent (comprising binary and ternary cross-linking agent)
The preparation process of diethylamine pentaacetic acid gadolinium meglumine targeted contrast agent and Omnipaque, Ultravist, iopamidol targeted contrast agent is identical with above-mentioned amidotrizoic acid targeted contrast agent basically with method.Just, four primary hydroxyls of iopamidol will be protected in advance, slough blocking group then at the appropriate time, but the guard method list of references of primary hydroxyl (Goerlach A, Kenia G and Geofrey AP.Bioconjugate Chem, 2:96,1991).
Animal experiment 1. tumor target direction contrast agents showed at lotus people pulmonary carcinoma nude mice model CT and MRI guiding scanning experimental result before tumor target direction contrast agent was clinical, during the CT enhanced ct scans, the CT value of using the tumor focus increase of common cardiografin contrast agent is with 65% of cardiografin-sulfadiazine cross-linking agent.During the MRI enhanced ct scans, the value added of tumor focus signal intensity is for being 61% of targeted contrast agent DTPA-Gd meglumine-sulfadiazine cross-linking agent with common contrast agent DTPA-Gd meglumine.Above result shows that tumor target direction contrast agent more can significantly improve the CT value or the MRI signal intensity of tumor focus than common contrast agent.2. tumor target direction contrast agent shows at rabbit original position hepatocarcinoma MODEL C T and MRI guiding scanning experimental result, when the CT value that liver lesion increases when using the cardiografin enhanced ct scans is to use cancer target Baryan cardiografin-sulfadiazine cross-linking agent 56%, cancer target Baryan to the raising of liver lesion density significantly greater than common contrast agent cardiografin.Also significantly greater than common magnetic contrast agent DTPA-Gd meglumine, it is 68% of cancer target magnetic contrast agent that common magnetic contrast agent increases the tumor focus signal intensity to MRI cancer target magnetic contrast agent DTPA-Gd meglumine-sulfadiazine cross-linking agent to the raising of liver lesion density.3. tumor target direction contrast agent acute toxinology experiment
By 40 Kunming white mice toxicological tests are shown, every caudal vein is injected cardiografin-sulfadiazine cross-linking agent 0.5ml (totally 20) and injection Diethylenetriamine five second gadolinium meglumines-sulfadiazine cross-linking agent 0.5ml (totally 20), observes a month no dead mouse.The technique effect of tumor target direction contrast agent of the present invention and advantage 1. tumor target direction contrast agents of the present invention are the alternative density (CT value and MRI signal intensity) that increases tumor focus when CT and MRI enhanced ct scans, and optimum focus density is only slightly risen or do not raise, thereby improve CT and MRI scanning resolution and specificity to the tumor focus diagnosis.2. tumor target direction contrast agent of the present invention is alternative CT value or the MRI signal intensity that increases mediastinum and the carcinous metastatic lymph node of intraperitoneal when CT and MRI enhanced ct scans, and struvite lymph node is not had obvious influence.Therefore to differentiating whether mediastinum and lymphonodi coeliaci exist neoplasm metastasis to have qualitative value, TNM divides interim being significant in the assessment tumor.3. tumor target direction contrast agent of the present invention has improved CT than common contrast agent and MRI scans resolution and the specificity that tumor focus is diagnosed, and has also avoided the isotopic contamination and the lower shortcoming of visualization resolution of tumour radiotherapy radionuclide imaging diagnosis.CT popularizes in overwhelming majority's (comprising at county level) above county level hospital at present, and MRI also comes into operation in considerable ground, city-level hospital.Therefore, tumor target direction contrast agent of the present invention will make the iconography technology have qualitative meaning in diagnosing tumor, thereby improve CT and the value of MRI scanning in diagnosing tumor, be the quantum jump progress in the medical imaging field.
The present invention is further elaborated by following examples, but does not limit the scope of the invention.Embodiment 1 DCC evaporation prepares amidotrizoic acid sulfadiazine binary cross-linking agent
Take by weighing AD powder 650mg and DCC 206mg is dissolved among the DMF, stir about 3h under the room temperature adds 250mg SD, continues the about 10h of stirring reaction.Because AD and SD all are dissolved in the ammonia spirit, their product also is dissolved in ammonia spirit, because DCC is insoluble to ammonia spirit, DCC is removed in available ammonia extraction, gets AD-SD binary cross-linking agent from ammonia spirit.Embodiment 2 activation fat legal systems are equipped with AD-SD
Take by weighing AD powder 650mg and DCC 206mg is dissolved among the DMF, stir about 3h under the room temperature adds 115mgNHS, and in 4 ℃, lucifuge under the anhydrous condition, continued stirring reaction about 10 hours.The active ester reactant is standby in-20 ℃ of storages under nitrogen protection.With gained active ester and the SD that waits molal quantity, under 4 ℃, under the lucifuge anhydrous condition, continued stirring reaction about 4 hours.The gained crude product is by the chromatographic column separation and purification.Promptly get AD-SD binary cross-linking agent.Embodiment 3 tumor target direction contrast agents are in the CT and the MRI guiding scanning experiment of lotus people pulmonary carcinoma nude mice model
With human lung carcinoma cell line SPC A-1 inoculation nude mice subcutaneous (10
7Cell/Mus), make lotus people pulmonary carcinoma nude mice model.Totally 20, be divided into 4 groups (5/every group), wherein 2 groups is observation group, 2 groups is matched group.Grow to the 1-1.5cm size when tumor and carry out that all nude mices carry out CT (10) respectively and MRI (10) is unenhanced, measure tumor focus CT value and MRI signal intensity and be respectively 31Hu and 281.Observation group (each 5) nude mice tail vein injection 0.25ml sulfadiazine-cardiografin cross-linking agent (containing the 150mg cardiografin) or 0.25ml sulfadiazine-DTPA-Gd meglumine cross-linking agent, nude mice of control group (each 5) tail vein injection 0.25ml contains same amount cardiografin or DTPA-Gd meglumine.Carry out CT and MRI enhanced ct scans after half an hour, measure tumor focus CT value and MRI signal intensity observation group and be respectively 68Hu and 431, matched group is respectively 55Hu and 372.Embodiment 4 tumor target direction contrast agents are in the CT and the MRI guiding scanning experiment of rabbit original position liver cancer model
With cell strain inoculation new zealand rabbit subcutaneous (10
8Cell), peel off Subcutaneous tumor after the one-tenth tumor and be cut into 2mm
3The size piece of tissue is implanted 16 new zealand rabbit livers of the same race respectively with modus operandi.Carry out following experiment after 1 month.Rabbit is divided into 4 groups (4 every group), and 2 groups of row CT are unenhanced, and 2 groups of row MRI are unenhanced, measure liver neoplasm focus CT value and MRI signal intensity and are respectively 37Hu and 170.In 2 groups of rabbits of CT scan 1 group from ear vein injection cancer target Baryan sulfadiazine-cardiografin cross-linking agent 2ml (containing the 1.2g cardiografin), another group injection 2ml cardiografin; MRI scans in 2 groups of rabbits 1 group from ear vein injection 2ml cancer target magnetic contrast agent sulfadiazine-DTPA-Gd meglumine cross-linking agent, the common magnetic contrast agent of another group injection 2ml DTPA-Gd meglumine.Carry out enhanced ct scans respectively, measure liver lesion CT value and MRI signal intensity, be respectively 96Hu and 821 at tumor target direction contrast agent, common contrast agent is respectively 70Hu and 613.
Claims (7)
1. tumor target direction contrast agent is characterized in that it is phlebography agent-close tumor material binary cross-linking agent that the phlebography agent used by computer-tomography (CT) or nuclear magnetic resonance (MRI) enhanced ct scans and close tumor material are connected into by chemical crosslink technique.
2. a tumor target direction contrast agent is characterized in that it is the phlebography agent-human serum albumin-close tumor material ternary cross-linking agent that is connected into by chemical crosslink technique by phlebography agent, close tumor material and human serum albumin that computer-tomography or nuclear magnetic resonance enhanced ct scans are used.
3. tumor target direction contrast agent as claimed in claim 1 or 2 is characterized in that the phlebography agent that described computer-tomography enhanced ct scans is used is cardiografin or Omnipaque or Ultravist or iopamidol.
4. tumor target direction contrast agent as claimed in claim 1 or 2 is characterized in that the phlebography agent that described nuclear magnetic resonance enhanced ct scans is used is the DTPA-Gd meglumine.
5. tumor target direction contrast agent as claimed in claim 1 or 2 is characterized in that described close tumor material is sulfadiazine, tetracycline, antitumor memebrane protein or growth factor receptors class monoclonal antibody.
6. the preparation method of tumor target direction contrast agent binary cross-linking agent as claimed in claim 1 is characterized in that having two kinds of methods:
Method A adopts dicyclohexylcarbodiimide (DCC) evaporation, and the carboxyl in the phlebography agent that described CT or MRI enhanced ct scans are used is by the effect of DCC, with ammonia (or amine) the effect generation binary cross-linking agent in the close tumor material.
Method B adopts active ester method, and carboxyl in the phlebography agent that described CT or MRI enhanced ct scans are used and N-hydroxy-succinamide generate the N-hydroxy-succinamide carboxylate under the DCC effect, and this ester and ammonia (or amine) effect generates the binary cross-linking agent.
7. the preparation method of tumor target direction contrast agent ternary cross-linking agent as claimed in claim 2; it is characterized in that at first on close tumor material, introducing dimaleoyl imino or iodoacetyl; on human serum albumin's molecule, introduce sulfydryl again; thereby the radical reaction of the two introducing makes close tumor material and human serum albumin crosslinked; and carboxyl or the reaction of its activate ester derivative in the amino freely phlebography agent that can use with CT or MR enhanced ct scans in human serum albumin's molecule, thereby obtain the ternary cross-linking agent.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US7750041B2 (en) | 2001-03-26 | 2010-07-06 | Bayer Schering Pharma Aktiengesellschaft | Preparation for the prophylaxis of restenosis |
| CN101347625B (en) * | 2007-07-20 | 2010-07-28 | 上海交通大学医学院附属瑞金医院 | Thrombus target contrast agent of nuclear magnetic resonance and preparation method thereof |
| CN101314049B (en) * | 2008-06-13 | 2010-11-10 | 许川山 | Novel targeted microbubble contrast medium |
| US8257305B2 (en) | 2002-09-20 | 2012-09-04 | Bayer Pharma Aktiengesellschaft | Medical device for dispensing medicaments |
| CN105879045A (en) * | 2016-04-13 | 2016-08-24 | 中国药科大学 | Albumin nanoparticles realizing co-delivery of antitumor drug and MRI (magnetic resonance imaging) contrast medium and preparation method of albumin nanoparticles |
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- 1998-01-24 CN CN 98110637 patent/CN1224622A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7750041B2 (en) | 2001-03-26 | 2010-07-06 | Bayer Schering Pharma Aktiengesellschaft | Preparation for the prophylaxis of restenosis |
| US8389043B2 (en) | 2001-03-26 | 2013-03-05 | Bayer Pharma Aktiengesellschaft | Preparation for restenosis prevention |
| US9066990B2 (en) | 2001-03-26 | 2015-06-30 | Bayer Intellectual Property Gmbh | Preparation for restenosis prevention |
| US8257305B2 (en) | 2002-09-20 | 2012-09-04 | Bayer Pharma Aktiengesellschaft | Medical device for dispensing medicaments |
| US8439868B2 (en) | 2002-09-20 | 2013-05-14 | Bayer Pharma AG | Medical device for dispersing medicaments |
| US9649476B2 (en) | 2002-09-20 | 2017-05-16 | Bayer Intellectual Property Gmbh | Medical device for dispersing medicaments |
| CN101347625B (en) * | 2007-07-20 | 2010-07-28 | 上海交通大学医学院附属瑞金医院 | Thrombus target contrast agent of nuclear magnetic resonance and preparation method thereof |
| CN101314049B (en) * | 2008-06-13 | 2010-11-10 | 许川山 | Novel targeted microbubble contrast medium |
| CN105879045A (en) * | 2016-04-13 | 2016-08-24 | 中国药科大学 | Albumin nanoparticles realizing co-delivery of antitumor drug and MRI (magnetic resonance imaging) contrast medium and preparation method of albumin nanoparticles |
| CN105879045B (en) * | 2016-04-13 | 2018-09-28 | 中国药科大学 | Antineoplastic transmits albumin nano granular and preparation method thereof altogether with MRI contrast agent |
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