Preparation method and application of microenvironment response type polymer prodrug co-delivery gel system

A polymer, responsive technology, applied in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc., can solve the problems of low selectivity, limited clinical application, poor water solubility, etc. Clear, high drug utilization, high drug loading effect

Pending Publication Date: 2021-11-23
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, many chemotherapeutic drugs are often less selective and poorly soluble in water, which greatly limits their clinical application.

Method used

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  • Preparation method and application of microenvironment response type polymer prodrug co-delivery gel system
  • Preparation method and application of microenvironment response type polymer prodrug co-delivery gel system
  • Preparation method and application of microenvironment response type polymer prodrug co-delivery gel system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of thiolated acid-responsive polymer prodrug

[0039]

[0040] 1,6-Hexanedithiol (22 μL, 0.143 mmol) was dissolved in N,N-dimethylformamide (DMF), and hydroxycamptothecin-vinyl ether acrylate-polyethylene oxide was added dropwise under nitrogen protection. Ethylene glycol complex (100 mg, 0.0357 mmol) was dissolved in DMF, and triethylamine (TEA) was added, and the reaction was stirred overnight at room temperature. After the reaction, the reaction liquid was precipitated with glacial ether, and the yield was 93.24%. Proton NMR spectrum such as figure 1 shown.

Embodiment 2

[0041] Example 2 Assembly and crosslinking of microenvironment-responsive polymer prodrugs

[0042] The polymer prodrug (1.0 mg, 0.357 μmol) was dissolved in absolute ethanol, and the solution was slowly added dropwise to high-purity water under ultrasonic conditions. Drug micelles. Polymer prodrug (1.0mg, 0.357μmol) was dissolved in absolute ethanol, mixed with ethanol solution (0.208mg, 0.214μmol) of MMP-9 sensitive polypeptide under nitrogen protection, then added triethylamine, at room temperature Stirring and reacting for 4 hours, the reaction solution was slowly added dropwise into high-purity water under ultrasonic conditions, and the obtained solution was continued to be sonicated, and then dialyzed in high-purity water to obtain a cross-linked tumor microenvironment-responsive polymer prodrug gel.

[0043] figure 2 It is the proton nuclear magnetic spectrum of the MMP-9 sensitive polypeptide (top) and its cross-linking reaction with HCPT-VEA-PEG-SH (bottom). The r...

Embodiment 3

[0044] Example 3 Encapsulation of TGF-β inhibitors

[0045] Add 2 μl of TGF-β inhibitor ethanol solution (5 mg / mL) to 2 mL of microenvironment-responsive polymer prodrug gel aqueous solution (0.5 mg / mL), alternately perform vortex mixing and ultrasonication three times each to complete drug loading . image 3 It is the particle size diagram of the polymer prodrug gel before and after cross-linking and after cross-linking and loading TGF-β inhibitor SB525334. The average particle size of the material before crosslinking was 142nm, and the particle size distribution was 0.18; the average particle size after crosslinking was 168nm, and the particle size distribution was 0.23; the average particle size after loading TGF-β inhibitor did not change much, being 165nm, the particle size distribution is 0.24.

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Abstract

The invention discloses a preparation method and application of a microenvironment response type polymer prodrug co-delivery gel system. Double bonds in an acid response type polymer prodrug are subjected to sulfhydrylation modification by disulfydryl or polysulfydryl micromolecules through a Michael addition reaction, then cross-linking is performed by a tumor microenvironment response type cross-linking agent of which two ends are connected with double bonds through the Michael addition reaction, and finally, nanogel is prepared through a solvent exchange method, and loaded into a medicine capable of adjusting the tumor microenvironment. Through structural modification and cross-linking drug loading of chemotherapeutic drugs, step-by-step fixed-point release of different drugs is realized, whole-body toxic and side effects of the drugs are reduced, and the synergistic effect of the different drugs is improved.

Description

Technical field: [0001] The invention relates to the preparation method and application of polymer materials science and pharmaceutical preparations, in particular to the preparation method and application of a microenvironment-responsive polymer prodrug co-delivery gel system. Background technique: [0002] Today, chemotherapeutic drugs have been widely used to prevent the proliferation, infiltration and metastasis of cancer cells. However, many chemotherapeutic drugs often have low selectivity and poor water solubility, which greatly limits their clinical application. In the past few decades, people have tried many methods to improve the application of this type of chemotherapy drugs, and various drug-loading systems such as polymer prodrugs, liposomes, polymer micelles, etc. have also been developed for Controlled release of such chemotherapeutic drugs. The microenvironment-responsive polymer prodrug co-delivery gel system based on amphiphilic polymer-drug conjugates co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K47/60A61K31/4745A61K45/06A61P35/00
CPCA61K9/06A61K47/60A61K31/4745A61K45/06A61P35/00A61K2300/00
Inventor 陈维王峥钟伊南黄德春
Owner CHINA PHARM UNIV
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