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MPEG-poly(L-glutamic acid-gamma-hydrazide)-PDMAPMA triblock copolymer, and synthesis method and application thereof

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 achieve therapeutic effects, stability, and complicated schemes, so as to improve drug effects and avoid enzymatic hydrolysis Effect

Inactive Publication Date: 2014-10-08
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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-gamma-hydrazide)-PDMAPMA triblock copolymer, and synthesis method and application thereof
  • MPEG-poly(L-glutamic acid-gamma-hydrazide)-PDMAPMA triblock copolymer, and synthesis method and application thereof
  • MPEG-poly(L-glutamic acid-gamma-hydrazide)-PDMAPMA triblock copolymer, and synthesis method and application thereof

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 invention discloses a synthesis method and an application of an mPEG-poly(L-glutamic acid-gamma-hydrazide)-PDMAPMA triblock copolymer. According to the invention, end methoxy polyethylene glycol is subjected to cystamine modification; a gamma-benzyl ester-L-glutamic acid-N-carboxyanhydride ring-opening polymerization reaction is initiated; with a carbodiimide method, a small-molecular RAFT polymerization chain-transfer agent is bonded to an obtained diblock copolymer; RAFT polymerization is carried out with N-(3-dimethylaminopropyl)methacrylamide as a monomer; and benzyl group is removed through hydrazinolysis, such that polyethylene glycol-poly(L-glutamic acid-gamma-hydrazide)-poly(N-(3-dimethylaminopropyl)methacrylamide) triblock copolymer is obtained. With the synthesis method provided by the invention, molecular weights and chain lengths of all blocks of polymers can be flexibly controlled. Reaction conditions are mild, and raw materials are easy to obtain. The copolymer has a characteristic that the copolymer is amphiphilic when loading adriamycin, such that the block copolymer can be self-assembled into nano-particles. The copolymer can load chemotherapeutic drugs and genetic drugs at a same time. Drug potency is high, and toxic and side effects are greatly reduced.

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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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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