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Preparation method and application of particle size-shrinking tumor-permeable nanosystem sensitive to fap-α enzyme and reducing environment

A FAP- and permeability technology, applied in the field of preparation of tumor-permeable nanosystems, can solve the problems of large toxic and side effects, single function, lack of targeting of drug delivery systems, etc., and achieve high targeting and good biocompatibility. The effect of simple and convenient synthesis process

Active Publication Date: 2019-11-22
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, the drug delivery systems used clinically still have the disadvantages of lack of targeting, high toxicity and side effects, single function, and difficulty in overcoming the biological barrier of the tumor microenvironment.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] In concrete implementation, the present invention can be realized by the following steps:

[0023] (1) Synthesis of reduction-sensitive nanoparticles (DOX-S-S-PAMAM):

[0024] ①Weigh 109mg of 2,2'-dithiodiacetic acid and 3ml of acetyl chloride as the connecting arm, put them in a flask, reflux in an oil bath at 65°C for 2 hours, concentrate the reactants and add 3 times pre-cooled diethyl ether, Cooling and crystallization, vacuum drying to obtain 2,2'-dithiodiacetic anhydride;

[0025] ② Weigh 0.3mmol DOX, 0.3mmol 4-dimethylaminopyridine (DMAP) and 0.3mmol 2,2'-dithiodiacetic anhydride and dissolve them in 5ml N,N-dimethylformamide (DMF); mix DOX and DMAP Mix the solution, add 20 μl triethylamine (TEA), add 2,2'-dithiodiacetic anhydride solution to the above solution, and react in the dark at 35°C for 8 hours, after the reaction stops, add 3 times pre-cooled diethyl ether, Cooling and crystallization, vacuum drying to obtain carboxylated doxorubicin (DOX-S-S-COOH); ...

Embodiment 2

[0030] The present invention can also be realized by the following steps in concrete implementation:

[0031] (1) Synthesis of reduction-sensitive nanoparticles (DOX-S-S-PAMAM):

[0032] ① Weigh 252mg of 3,3'-dithiodipropionic acid and 6.0ml of acetyl chloride as the connecting arm, put them in a flask, reflux in an oil bath at 65°C for 4 hours, concentrate the reactants and add 3.5 times pre-cooled Diethyl ether, cooling and crystallization, and vacuum drying to obtain 3,3'-dithiodipropionic anhydride;

[0033] ② Weigh 0.6mmol DOX, 0.6mmol 4-dimethylaminopyridine (DMAP) and 0.6mmol 3,3'-dithiodipropionic anhydride and dissolve them in 9ml N,N-dimethylformamide (DMF); then the DOX solution Mix with DMAP solution, then add 60 μl triethylamine (TEA) solution, and finally add 3,3'-dithiodipropionic anhydride solution, react at 40°C in the dark for 12 hours, add 3.5 times pre-cooled ether after the reaction stops , cooling and crystallization, and vacuum drying to obtain carboxy...

Embodiment 3

[0038] In specific implementation, the present invention can also be realized by the following steps:

[0039] (1) Synthesis of reduction-sensitive nanoparticles (DOX-S-S-PAMAM):

[0040] ① Weigh 420mg of 3,3'-dithiodipropionic acid and 9ml of acetyl chloride as the connecting arm, put them in a flask, reflux in an oil bath at 65°C for 5h, concentrate the reactants and add 4 times pre-cooled diethyl ether , cooling and crystallization, and vacuum drying to obtain 3,3'-dithiodipropionic anhydride;

[0041] ② Weigh 0.9mmol DOX, 0.9mmol 4-dimethylaminopyridine (DMAP) and 0.9mmol 3,3'-dithiodipropionic anhydride and dissolve them in 14ml dimethyl sulfoxide (DMSO); mix DOX solution and DMAP solution , add 80 μl triethylamine (TEA), add 3,3'-dithiodipropionic anhydride solution to the above solution, and react in the dark at 45°C for 24 hours, add 4 times pre-cooled ether after the reaction stops, cool and analyze crystal, vacuum-dried to obtain carboxylated doxorubicin (DOX-S-S-C...

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Abstract

The invention relates to a preparation method and application of a shrinking particle size type tumor penetrating nano system sensitive to FAP-Alpha (fibroblast activation protein alpha) enzyme and reducing environment, and effectively solves the problem that a traditional drug delivery system has poor targeting performance, high toxic and side effects, single functionality, poor penetrating performance and difficulty in overcoming tumor microenvironment bio-barrier. According to the technical scheme to solve the problem, doxorubicin is connected with polyamidoamine through disulfide bonds as linker arms to form reduction-sensitive nanoparticles, the nanoparticles are connected with polypeptides linker arms sensitive to FAP-Alphaj to form the shrinking particle size type tumor penetrating nano system sensitive to FAP-Alpha enzyme and reducing environment; the shrinking particle size type tumor penetrating nano system sensitive to FAP-Alpha enzyme and reducing environment has the advantages of good biocompatibility, sensitiveness to enzymes and reducing environments, and capability to effectively overcome tumor microenvironment bio-barrier, and belongs to innovation on drug preparations for tumor therapy.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method and application of a tumor-permeable nanometer system with particle size contraction that is sensitive to FAP-α enzyme and reducing environment. Background technique [0002] In recent years, the incidence of malignant tumors has shown an upward trend. Malignant tumors are currently one of the leading causes of death in the world and have become a major category of diseases that seriously endanger human life and health. Therefore, various new anti-tumor drugs and nano drug delivery systems Came into being. However, the therapeutic efficiency of many anticancer drugs and drug delivery systems always fails to achieve the expected effect, mainly due to the biological barrier effect of the tumor microenvironment, which prevents anticancer drugs from reaching the tumor site efficiently. Among them, the most obvious barrier function is the cancer-associated fibroblasts sur...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/69A61K47/64A61K31/704A61P35/00C08G83/00
CPCA61K31/704C08G83/006
Inventor 侯琳张振中郝丽莎张银玲郑亚珍
Owner ZHENGZHOU UNIV
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