Mpeg-poly(l-glutamic acid-γ-hydrazide)-pdmapma triblock copolymer and its synthesis method and application

A technology of block copolymers and synthesis methods, which is applied in the field of biomedical materials, can solve problems such as constraints, the impossibility of a single drug to obtain therapeutic effects, stability, and complicated schemes, so as to avoid enzymatic hydrolysis and improve drug effects. Effect

Inactive Publication Date: 2016-08-17
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

A large number of studies and clinical practice have shown that cancer is a very complex disease with heterogeneity and drug resistance, and it is unlikely that a single agent will achieve the desired therapeutic effect
The sequential combination of drugs with different mechanisms of action in clinical cancer chemotherapy regimens has made encouraging progress in overcoming drug resistance and increasing efficacy, but its application is restricted by problems such as compatibility, stability, and complex regimens.

Method used

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  • Mpeg-poly(l-glutamic acid-γ-hydrazide)-pdmapma triblock copolymer and its synthesis method and application
  • Mpeg-poly(l-glutamic acid-γ-hydrazide)-pdmapma triblock copolymer and its synthesis method and application
  • Mpeg-poly(l-glutamic acid-γ-hydrazide)-pdmapma triblock copolymer and its synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1) Synthesis of γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride (BLG-NCA):

[0045] Add L-glutamic acid-γ-benzyl ester into anhydrous tetrahydrofuran, then add triphosgene under nitrogen atmosphere, then react at 50°C until a clear solution is formed, remove most of the solvent under reduced pressure to concentrate the solvent, and finally concentrate to obtain The reaction system was precipitated and recrystallized in anhydrous n-hexane to obtain BLG-NCA; wherein, the molar ratio of L-glutamic acid-γ-benzyl ester to triphosgene was 1:0.367, and every 100mL of anhydrous tetrahydrofuran Add 10 g of L-glutamic acid-γ-benzyl ester;

[0046] 2) Synthesis of cystaminated methoxypolyethylene glycol:

[0047] 2.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 2000, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and react under a nitrogen atmosphere at 85°C For 48 hours, precipitate 3 times in anhydrous n-hexan...

Embodiment 2

[0064] 1) Synthesis of γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride (BLG-NCA):

[0065] Add L-glutamic acid-γ-benzyl ester into anhydrous tetrahydrofuran, then add triphosgene under nitrogen atmosphere and react at 50°C to form a clear solution, remove most of the solvent under reduced pressure to concentrate the solvent, and finally concentrate the obtained The reaction system was precipitated and recrystallized in anhydrous n-hexane to obtain BLG-NCA; wherein, the molar ratio of L-glutamic acid-γ-benzyl ester to triphosgene was 1:0.4, and every 100mL of anhydrous tetrahydrofuran was added 15 g of L-glutamic acid-γ-benzyl ester;

[0066] 2) Synthesis of cystaminated methoxypolyethylene glycol:

[0067] 2.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 4000, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and react under a nitrogen atmosphere at 85°C For 48 hours, precipitate 3 times in anhydrous n-hexane, ...

Embodiment 3

[0078] 1) Synthesis of γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride (BLG-NCA):

[0079] Add L-glutamic acid-γ-benzyl ester into anhydrous tetrahydrofuran, then add triphosgene under nitrogen atmosphere, then react at 50°C until a clear solution is formed, remove most of the solvent under reduced pressure to concentrate the solvent, and finally concentrate to obtain The reaction system was precipitated and recrystallized in anhydrous n-hexane to obtain BLG-NCA; wherein, the molar ratio of L-glutamic acid-γ-benzyl ester to triphosgene was 1:0.383, and every 100mL of anhydrous tetrahydrofuran Add 12g of L-glutamic acid-γ-benzyl ester;

[0080] 2) Synthesis of cystaminated methoxypolyethylene glycol:

[0081] 2.1) Dissolve dry methoxy-terminated polyethylene glycol with a molecular weight of 1000, dibutyltin dilaurate and 2,2'-dithiodiethylisocyanate in anhydrous toluene, and store at 85°C under a nitrogen atmosphere. React for 48 hours, precipitate 3 times in anhydrous n...

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Abstract

The synthetic method of mPEG-poly(L-glutamic acid-gamma-hydrazide)-PDMAPMA three-block copolymer and its synthetic method and application, first carry out cystamination modification to terminal methoxy polyethylene glycol, then Initiate gamma-benzyl ester-L-glutamic acid-N-carboxyl ring internal anhydride ring-opening polymerization, and then use the carbodiimide method to bond the small molecule RAFT polymer chain transfer agent to the obtained diblock copolymer, Finally, RAFT polymerization is carried out with N-(3-dimethylaminopropyl)methacrylamide as a monomer, and then the benzyl group is removed by hydrazinolysis to obtain polyethylene glycol-poly(L-glutamic acid-γ-acyl hydrazine)-poly(N-(3-dimethylaminopropyl)methacrylamide) triblock copolymer. The synthesis method of the present invention can flexibly control the molecular weight and chain length of each segment of the polymer, the reaction conditions are mild, and the raw materials are easy to get. It is loaded with chemotherapy drugs and gene drugs at the same time, with high drug efficacy and greatly reduced toxic and side effects.

Description

technical field [0001] The invention belongs to the field of biomedical materials, in particular to mPEG-poly(L-glutamic acid-γ-hydrazide)-PDMAPMA triblock copolymer and its synthesis method and application. Background technique [0002] Chemotherapy is the basic strategy of clinical tumor treatment, which uses cytotoxic drugs to kill tumor cells to achieve the purpose of treating tumors. Currently, commonly used chemotherapeutic drugs include doxorubicin, epirubicin, paclitaxel, docetaxel, camptothecin, 10-hydroxycamptothecin, vinblastine, and vincristine. These cytotoxic drugs not only have a short half-life in vivo, are poorly soluble in water, and have poor selectivity, resulting in low bioavailability, but also have serious side effects on normal tissues / cells. Therefore, improving curative effect and reducing toxic and side effects have always been the goals pursued by the basic research and clinical application of cancer chemotherapy. In order to achieve this goal, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08F293/00C08F220/60C08F8/00C08G69/48C08G69/40C08G65/48A61K47/48A61K48/00A61P35/00A61K31/704
Inventor 钱军民徐明辉胥伟军刘茸茸王红洁
Owner XI AN JIAOTONG UNIV
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