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Three-arm star hydrophilic copolymer, and synthesis method and application thereof

A technology of a hydrophilic copolymer and a synthesis method, applied in the field of biomedical materials, can solve the problems of difficulty in fully exerting drug efficacy, slow drug release rate, etc., and achieve the effects of low critical micelle concentration, improved efficacy, and mild reaction conditions.

Inactive Publication Date: 2014-09-17
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the segments of the block copolymer are connected by ester bonds and urethane bonds, there is no stimuli-responsive dissociation mechanism, the drug release rate is slow, and it is difficult to fully exert the drug effect

Method used

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  • Three-arm star hydrophilic copolymer, and synthesis method and application thereof
  • Three-arm star hydrophilic copolymer, and synthesis method and application thereof
  • Three-arm star hydrophilic copolymer, and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] 1) Synthesis of γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride (BLG-NCA):

[0048] 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, then concentrate under reduced pressure to remove most of the solvent to concentrate the solvent, and finally to Add anhydrous n-hexane to the reaction system obtained after concentration to precipitate, and recrystallize the obtained precipitate with anhydrous n-hexane to obtain γ-benzyl ester-L-glutamic acid-N-carboxyl anhydride (BLG-NCA) ; Wherein, the molar ratio of L-glutamic acid-γ-benzyl ester to triphosgene is 1:0.35, and 10g of L-glutamic acid-γ-benzyl ester is dissolved in every 100 milliliters of anhydrous tetrahydrofuran;

[0049] 2) Synthesis of three-arm poly(L-glutamate-γ-benzyl ester) (tPBLG):

[0050] Reflux tris(2-aminoethyl)amine through calcium hydride for 12 hours, and distill under reduced pressu...

Embodiment 2

[0067] 1) Same as step 1) in Example 1.

[0068] 2) Synthesis of three-arm poly(L-glutamate-γ-benzyl ester) (tPBLG):

[0069] Reflux tris(2-aminoethyl)amine through calcium hydride for 12 hours, and distill under reduced pressure under nitrogen atmosphere to obtain anhydrous tris(2-aminoethyl)amine, then dissolve anhydrous tris(2-aminoethyl)amine In anhydrous chloroform, add BLG-NCA under a nitrogen atmosphere, stir to form a uniform solution, and react at 40°C for 60 hours; after the reaction, the obtained reaction solution is precipitated with cold ether and washed with ethanol, and vacuum-dried to obtain a white powder tPBLG; wherein, the molar ratio of anhydrous tris(2-aminoethyl)amine and BLG-NCA is 1:60, and 5g of BLG-NCA is dissolved in every 100 milliliters of anhydrous chloroform;

[0070] 3) Synthesis of three-arm poly(L-glutamic acid-γ-benzyl ester) macromolecular RAFT chain transfer agent:

[0071] The tPBLG was azeotropically dewatered with toluene under nitroge...

Embodiment 3

[0080] 1) Same as step 1) in Example 1.

[0081] 2) Synthesis of three-arm poly(L-glutamate-γ-benzyl ester) (tPBLG):

[0082] Reflux tris(2-aminoethyl)amine through calcium hydride for 12 hours, and distill under reduced pressure under nitrogen atmosphere to obtain anhydrous tris(2-aminoethyl)amine, then dissolve anhydrous tris(2-aminoethyl)amine In anhydrous tetrahydrofuran, add BLG-NCA under a nitrogen atmosphere, stir to form a uniform solution, and react at 40°C for 48 hours; after the reaction, the obtained reaction solution is precipitated with cold ether and washed with ethanol, and vacuum-dried to obtain a white powder tPBLG; wherein, the molar ratio of anhydrous tris(2-aminoethyl)amine and BLG-NCA is 1:45, and 5g of BLG-NCA is dissolved in every 100 milliliters of anhydrous tetrahydrofuran;

[0083] 3) Synthesis of three-arm poly(L-glutamic acid-γ-benzyl ester) macromolecular RAFT chain transfer agent:

[0084]The tPBLG was azeotropically dewatered with toluene unde...

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Abstract

The invention relates to a three-arm star hydrophilic copolymer, and a synthesis method and application thereof. The synthesis method comprises the following steps: initiating gamma-benzyl-L-glutamate-N-carboxy-alpha-amino acid anhydride ring-opening polymerization reaction by using a three-element primary amine inner core, and bonding small-molecule RAFT polymeric chain transfer agent to three terminated amino groups of the star polymer through a carbodiimide method, thus obtaining large-molecule RAFT chain transfer agent; and performing RAFT polymerization by using N-(3-dimethylaminopropyl) and N-hydroxymethyl acrylamide as monomers, finally reacting the hydroxyl group of the N-hydroxymethyl acrylamide component in the copolymer with isocyanated methyl-terminated polyethyleneglycol to realize connection to the polyethyleneglycol via a disulfide bond, and performing hydrazinolysis treatment to obtain the required three-arm star hydrophilic copolymer. According to the method, the molecular weight and chain length of each polymer component can be flexibly controlled, the reaction conditions are mild, and the raw materials are accessible; the synthesized polymer can improve the drug effect and reduce the toxic or side effect; and meanwhile, when loading amycin and gene-based drugs, the polymer realizes the synergic antitumor treatment effect.

Description

technical field [0001] The invention belongs to the field of biomedical materials, and in particular relates to a three-arm star-shaped hydrophilic copolymer and its synthesis method and application. Background technique [0002] Chemotherapy based on cytotoxic drugs is one of the main strategies for the treatment of malignant tumors. However, cytotoxic drugs usually have high cytotoxicity, poor water solubility and no bioselectivity, and can kill tumor cells and normal cells at the same time, with serious side effects. Since the curative effect and side effects of chemotherapy are strongly positively correlated with the drug dose, it is difficult to improve the therapeutic effect by increasing the drug concentration. What's more serious is that almost all tumor cells will develop multidrug resistance during chemotherapy with cytotoxic drugs. These have become the main obstacles restricting the success of chemotherapy. Many studies in recent years have shown that the use ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00C08F293/00C08F220/60C08F220/58C08G69/48C08G65/48A61K47/48A61K48/00A61K31/704A61P35/00
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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