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Reduction-response self-depolymerization graft polymer based on polysaccharide as well as preparation method and application thereof

A graft polymer and polymer technology, applied in the field of polysaccharide-based reduction-response self-depolymerization graft polymer and its preparation, can solve the problems of macromolecular hydrophobic polymers that are not easy to metabolize, long-term toxicity, and cumbersome synthesis steps , to achieve the effect of high efficiency, non-toxicity and promotion of drug release

Active Publication Date: 2018-07-31
温岭汉德高分子科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the traditional amphiphilic reduction-responsive polymer carrier can only be decomposed into different polymers under the action of the reducing agent glutathione, and the macromolecular hydrophobic polymer is not easy to be metabolized, so it accumulates in the body, and there is a risk of long-term toxicity. ; In addition, conventional reduction-responsive polymers require a large amount of glutathione to cut disulfide bonds, thereby causing the dissociation of micelles to achieve drug release
The click reaction has been widely concerned since it was proposed in 2001, and has been widely used in the modification of polysaccharides. However, the conventional click reaction requires copper ions to catalyze, and copper ions are difficult to remove in the system, which will cause toxicity in biomedical applications. and restricted applications
Although there are many click reactions based on copper-free catalysis, their wide application is limited due to the cumbersome synthesis steps.

Method used

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  • Reduction-response self-depolymerization graft polymer based on polysaccharide as well as preparation method and application thereof
  • Reduction-response self-depolymerization graft polymer based on polysaccharide as well as preparation method and application thereof
  • Reduction-response self-depolymerization graft polymer based on polysaccharide as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0041] A method for preparing polysaccharide-based reduction-responsive self-depolymerization graft polymers, the synthetic route is detailed in figure 1 , including the following steps:

[0042] 1) Dissolve polysaccharide and 3-azidopropionic acid in deionized water, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, at 40 The reaction was carried out at -60°C for 24-72 hours, then dialyzed and freeze-dried to obtain polysaccharide-azide derivatives.

[0043] Wherein, the solid-to-liquid ratio of the polysaccharide, 3-azidopropionic acid, deionized water, 1-ethyl-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide 1g: 0.1-0.5g: 20mL: 0.5g: 0.3g.

[0044] 2) dissolving propiolic acid and bis(2-hydroxyethyl) disulfide in tetrahydrofuran, then adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine, reacting overnight at room temperature, filtering to remove the white precipitate, and using Silica gel column purification to obtain alkyne-...

Embodiment 1

[0056] (1) Dissolve 1g dextran, 0.3g 3-azidopropionic acid and 0.3g N-hydroxysuccinimide in 20mL deionized water, then add 0.5g 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide was reacted at 45°C for 48 hours, dialyzed with a dialysis bag for three days, and freeze-dried to obtain dextran-azide derivatives.

[0057] (2) Dissolve 2g of propiolic acid and 10g of bis(2-hydroxyethyl)disulfide in 20mL of tetrahydrofuran, then add 7.6g of dicyclohexylcarbodiimide and 0.4g of 4-dimethylaminopyridine, and react overnight at room temperature , filtered to remove the white precipitate, rotary evaporated to remove tetrahydrofuran, and then purified with a silica gel column (mobile phase was ethyl acetate and n-hexane) to obtain the product alkyne-disulfide bond-hydroxyl.

[0058] (3) Dissolve 1g of 4-aminobenzyl alcohol in a mixed solution of 15mL tetrahydrofuran / saturated aqueous sodium bicarbonate solution, then add 1.2mL phenyl chloroformate, react for 1h, add 50mL ethyl acetate, wash w...

Embodiment 2

[0063] (1) Dissolve 1 g of sodium alginate, 0.5 g of 3-azidopropionic acid and 0.3 g of N-hydroxysuccinimide in 20 mL of deionized water, then add 0.5 g of 1-ethyl-(3-dimethyl Aminopropyl) carbodiimide was reacted at 60°C for 24 hours, dialyzed with a dialysis bag for three days, and freeze-dried to obtain sodium alginate-azide derivatives.

[0064] (2) Dissolve 2g of propiolic acid and 10g of bis(2-hydroxyethyl)disulfide in 20mL of tetrahydrofuran, then add 7.6g of dicyclohexylcarbodiimide and 0.4g of 4-dimethylaminopyridine, and react overnight at room temperature , filtered to remove the white precipitate, rotary evaporated to remove tetrahydrofuran, and then purified with a silica gel column (mobile phase was ethyl acetate and n-hexane) to obtain the product alkyne-disulfide bond-hydroxyl.

[0065] (3) Dissolve 1g of 4-aminobenzyl alcohol in a mixed solution of 15mL tetrahydrofuran / saturated aqueous sodium bicarbonate solution, then add 1.2mL phenyl chloroformate, react fo...

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Abstract

The invention relates to the field of medical high molecular materials, and discloses a reduction-response self-depolymerization graft polymer based on a polysaccharide as well as a preparation methodand application thereof. The structure of the reduction-response self-depolymerization polymer provided by the invention is a polysaccharide-graft(disulfide bond)-self-depolymerization polymer; the polymer can be triggered in a state of a low-concentration reducer to be degraded into a small molecule; the release and metabolism, from a body, of a medicine are more easily promoted. In the preparation method, the polysaccharide and a self-depolymerization polymer are coupled through a copper-free click reaction; the reaction is efficient and nontoxic. In addition, the reduction-response self-depolymerization graft polymer based on the polysaccharide can be used for forming a micelle with a core-shell structure in a self-assembly manner in water; the micelle can be used for loading a hydrophobic chemotherapeutic drug; due to the favorable biocompatibility and stealth performance of the polysaccharide, the effective aggregation at a tumor location is achieved through an EPR (Enhanced Permeability and Retention) effect; afterwards, the self-depolymerization graft polymer is triggered by a reducing environment of the tumor part to carry out self-depolymerization; the medicine is quicklyreleased, and the curative effect is exerted.

Description

technical field [0001] The invention relates to the field of medical polymer materials, in particular to a polysaccharide-based reduction-response self-depolymerization graft polymer and its preparation method and application. Background technique [0002] Cancer seriously endangers human life and health, and has been listed as the "second killer" facing human beings after cardiovascular disease. Chemotherapy is a main treatment method, but the effect of chemotherapy is not ideal due to the serious side effects of chemotherapy drugs. [0003] Nanotechnology is an emerging and highly interdisciplinary comprehensive subject. Nanoparticles have the advantages of quantum size effect, large specific surface area, and easy surface modification. They have many advantages in the application of drug delivery. Using nanoparticles to load chemotherapy drugs to reach the tumor site, triggering the structural change of the nanoparticles through the reducing environment of the tumor site...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00A61K9/107A61K47/36
CPCA61K9/1075A61K47/36C08G81/00
Inventor 蔡国华
Owner 温岭汉德高分子科技有限公司
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