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pH/reduction dual sensitive hydrophilic copolymer drug carrier as well as synthesis method and application thereof

A hydrophilic copolymer, double sensitive technology, applied in the direction of drug combination, pharmaceutical formulation, genetic material components, etc., to achieve the effect of protecting genetic material, low critical micelle concentration, and avoiding micelle instability

Inactive Publication Date: 2014-09-10
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, cationic polymer carriers have molecular weight positively related transfection efficiency and cytotoxicity, so it is very important to control their molecular weight

Method used

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  • pH/reduction dual sensitive hydrophilic copolymer drug carrier as well as synthesis method and application thereof
  • pH/reduction dual sensitive hydrophilic copolymer drug carrier as well as synthesis method and application thereof
  • pH/reduction dual sensitive hydrophilic copolymer drug carrier as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 1) Synthesis of N-tert-butoxycarbonylacrylohydrazide:

[0046] Dissolve tert-butoxycarbonylhydrazine in water at 0°C to form a 1mol / L solution, and then add a chloroform solution of acryloyl chloride with a concentration of 5mol / L dropwise within 30 minutes under vigorous stirring, while using 2mol / L for hydrogen oxidation Adjust the pH value to 8-9 with sodium aqueous solution, and then react at room temperature for 10 hours. Finally, the obtained product is extracted with dichloromethane, dried and recrystallized to obtain N-tert-butoxycarbonyl acrylic hydrazide; wherein, tert-butoxycarbonyl The molar ratio of hydrazine to acryloyl chloride in the chloroform solution of acryloyl chloride is 1:1.1; and the recrystallization adopts dichloromethane recrystallization;

[0047] 2) Synthesis of poly(N-tert-butoxycarbonylacrylhydrazide) macromolecular RAFT polymer chain transfer agent:

[0048] Dissolve S,S'-bis(α,α'-dimethyl-α″-acetic acid) trithiocarbonate, N-tert-butoxyc...

Embodiment 2

[0063] 1) Synthesis of N-tert-butoxycarbonylacrylohydrazide:

[0064] Dissolve tert-butoxycarbonylhydrazine in water at 2°C to form a 1mol / L solution, and then add a solution of acryloyl chloride in methylene chloride with a concentration of 5mol / L dropwise within 30 minutes under vigorous stirring, while using 2mol / L Sodium hydroxide aqueous solution adjusts the pH value to 8-9, and then reacts at room temperature for 8 hours, and finally extracts the obtained product through dichloromethane, dries and recrystallizes to obtain N-tert-butoxycarbonylacrylhydrazide; among them, tert-butyl The molar ratio of oxycarbonyl hydrazine to the acryloyl chloride in the dichloromethane solution of acryloyl chloride is 1:1.1; and the recrystallization adopts dichloromethane recrystallization;

[0065] 2) Synthesis of poly(N-tert-butoxycarbonylacrylhydrazide) macromolecular RAFT polymer chain transfer agent:

[0066] Dissolve S,S'-bis(α,α'-dimethyl-α″-acetic acid) trithiocarbonate, N-tert-...

Embodiment 3

[0076] 1) Synthesis of N-tert-butoxycarbonylacrylohydrazide:

[0077] Dissolve tert-butoxycarbonylhydrazine in water at 4°C to form a 1mol / L solution, and then add a dioxane solution of acryloyl chloride with a concentration of 5mol / L dropwise within 30 minutes under vigorous stirring, while using 2mol / L The sodium hydroxide aqueous solution adjusts the pH value to 8-9, and then reacts at room temperature for 4 hours, and finally the obtained product is extracted with dichloromethane, dried and recrystallized to obtain N-tert-butoxycarbonylacrylhydrazide; wherein, The molar ratio of tert-butoxycarbonylhydrazine to acryloyl chloride in dioxane solution of acryloyl chloride is 1:1.1; and the recrystallization adopts dichloromethane for recrystallization;

[0078] 2) Synthesis of poly(N-tert-butoxycarbonylacrylhydrazide) macromolecular RAFT polymer chain transfer agent:

[0079] S,S'-bis(α,α'-dimethyl-α″-acetic acid) trithiocarbonate, N-tert-butoxycarbonylacrylhydrazide and 4,4'...

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Abstract

The invention relates to a pH / reduction dual sensitive hydrophilic copolymer drug carrier as well as a synthesis method and application thereof. S,S'-bis(alpha, alpha'-dimethyl-alpha''-acetic acid) trithiocarbonate is taken as a chain transfer agent, RAFT (reversible additive fragment transfer) polymerization is carried out on N-t-butyloxycarboryl propylene hydrazine, N-(3-dimethylamine propyl) methacrylamide and N-hydroxymethyl acrylamide in two steps, reaction is carried out on hydroxyl on N-hydroxymethyl acrylamide and methoxyl polyethylene glycol at an isocyanic acid esterification end, polyethylene glycol is connected by virtue of a disulfide bond, and the target product, namely pH / reduction dual sensitive hydrophilic copolymer drug carrier, is obtained after a protecting group is removed. The pH / reduction dual sensitive hydrophilic copolymer drug carrier can load adriamycin and a gene drug at the same time; meanwhile, a hydrophilic polyethylene glycol shell can protect gene substance, long circulation is realized, a disulfide bond connected with polyethylene glycol is beneficial to escape of endosome of drug-carrier, the copolymer after being loaded with a drug can be self assembled into nanomicelle in water, bioavailability of the drug can be improved, and toxic and side effects can be reduced. The copolymer synthesis method provided by the invention has the advantages that molecular weight of each segment and quantity of polyethylene glycol segments can be flexibly adjusted and reaction conditions are mild.

Description

technical field [0001] The invention belongs to the field of biomedical materials, in particular to a pH / reduction double-sensitive hydrophilic copolymer drug carrier and its synthesis method and application. Background technique [0002] Malignant tumors have become common and frequently-occurring diseases that seriously endanger human health. The main treatment methods currently used are surgery, radiotherapy and chemotherapy. Chemotherapy is an inevitable choice when surgery is ineffective. Chemotherapy refers to the method of using cytotoxic drugs to treat tumors. However, the curative effect of tumor chemotherapy has a strong dose-dependence, serious side effects, and multidrug resistance of tumor cells, which have become the main obstacles restricting the success of tumor chemotherapy. Tumor treatment is the most challenging worldwide problem in contemporary medical science. Recent studies have shown that loading chemotherapeutic drugs in a certain form of carrier ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/48A61K48/00A61P35/00C08G81/02C08F293/00C08F220/60C08F220/58C08G65/48
Inventor 徐明辉钱军民胥伟军柳雪峰王红洁
Owner XI AN JIAOTONG UNIV
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