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An acid-responsive cross-linked polymer prodrug and its preparation method and application

A cross-linked polymer technology, which is applied in pharmaceutical formulation, drug combination, drug delivery, etc., can solve the problems of low delivery efficiency and drug leakage, achieve good biocompatibility, small side effects, and overcome the problems of easy leakage Effect

Active Publication Date: 2021-11-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The acid-responsive cross-linked polymer prodrug is simple to prepare, has a clear structure, and has a high drug loading rate. Cross-linking overcomes the defects of easy leakage of drugs in the body and low delivery efficiency in the prior art

Method used

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  • An acid-responsive cross-linked polymer prodrug and its preparation method and application
  • An acid-responsive cross-linked polymer prodrug and its preparation method and application
  • An acid-responsive cross-linked polymer prodrug and its preparation method and application

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Embodiment 1P

[0055] The synthesis of embodiment 1PEG-2VEA-HCPT

[0056] (1) Synthesis of small molecule vinyl ether acrylate (VEA)

[0057] The synthetic route of small molecule VEA is as follows:

[0058]

[0059] Ethylene glycol monovinyl ether (150ml, 1.73mol) was dissolved in 1.2L of dichloromethane, and 310mL of triethylamine (TEA) was added, and acryloyl chloride (168mL, 1.67mol) was added dropwise in an ice bath. After the dropwise addition, react at room temperature for 8h. After the reaction, the reaction liquid was extracted three times with aqueous sodium carbonate solution, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo for 6 h. The concentrated product was distilled under reduced pressure, and the fraction with a steam temperature of 56°C was collected to obtain a colorless liquid with a pungent odor, vinyl ether acrylate, with a yield of 63.2%. Proton NMR spectrum such as figure 1 show...

Embodiment 2P

[0068] The synthesis of embodiment 2PEG-2VEMA-HCPT

[0069] (1) Synthesis of small molecule vinyl ether methacrylate (VEMA)

[0070] The synthetic route of the small molecule compound VEMA is as follows:

[0071]

[0072] Ethylene glycol monovinyl ether (150ml, 1.73mol) was dissolved in 1.2L of dichloromethane, and 310mL of triethylamine (TEA) was added, and methacryloyl chloride (168mL, 1.49mol) was added dropwise in an ice bath . After the dropwise addition, react at room temperature for 8h. After the reaction, the reaction liquid was extracted three times with aqueous sodium carbonate solution, and the organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and dried in vacuo for 6 h. The concentrated product was distilled under reduced pressure, and the fraction with a steam temperature of 58°C was collected to obtain a colorless liquid with a pungent odor, vinyl ether methacrylate, with a yield of 51.6%. Proton NMR s...

Embodiment 3

[0081] The preparation of embodiment 3 polymer prodrug micelles (PEG-2VEA-HCPT)

[0082] Polymer prodrug micelles (PEG-2VEA-HCPT) were prepared by solvent exchange method. Under ultrasonic conditions, 0.1 mL of ethanol solution (20 mg / mL) of polymer prodrug PEG-2VEA-HCPT was slowly added to 2 mL of high-purity water, and the resulting mixed solution was continued to be ultrasonicated for half an hour. The assembled micelles were mixed with photoinitiator I2959 (mass fraction of polymer prodrug 5%), and dialyzed in high-purity water for 2 hours after ultraviolet irradiation for 15 minutes. Figure 5 is the particle size characterization diagram of polymer prodrug micelles (PEG-2VEA-HCPT) before and after crosslinking. The results showed that the average particle size of prodrug micelles before cross-linking was 180nm, and the particle size distribution was 0.22; after cross-linking, the average particle size of the micelles was 170nm, and the particle size distribution was 0.1...

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Abstract

The invention discloses an acid-responsive crosslinked polymer prodrug and its preparation method and application. The acid-responsive crosslinked polymer prodrug is mainly composed of vinyl alkyl ether acrylate monomers and derivatives thereof The drug is linked with a hydroxyl-containing chemotherapeutic drug through an acid-responsive acetal bond to form a drug-small molecule complex, and then connected with a thiolated PEG through a Michael addition reaction to obtain the acid-responsive cross-linked polymer prodrug. Compared with the prior art, the present invention prepares acid-responsive cross-linked polymer prodrug micelles with high drug loading and high stability by modifying chemotherapeutic drugs, which has broad application prospects in antitumor.

Description

technical field [0001] The invention relates to an acid-responsive cross-linked polymer prodrug and its preparation method and application, belonging to the technical fields of polymer materials and pharmaceutical preparations. Background technique [0002] The design of the carrier system is an important challenge for the application of poorly soluble chemotherapeutic drugs such as paclitaxel (PTX) and doxorubicin (DOX). In the past few decades, various biocompatible nanosystems such as polymeric prodrugs, liposomes, polymeric micelles, vesicles, and polymeric nanoparticles have been developed for poorly soluble chemotherapy. Safe and controlled release of drugs. For example, paclitaxel prodrugs can bind paclitaxel to hydrophilic polymers such as polyethylene glycol (PEG), poly[N-(2-hydroxypropyl)methacrylamide, ] (PHPMA), poly(L-glutamic acid) (PGlu) and hyaluronic acid. It is worth noting that PHPMA-PTX (PNU166945) and PGlu-PTX (CT-2103, Xyotax) have entered clinical p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K47/69A61K31/4745A61P35/00
CPCA61K31/4745A61K47/60A61K47/6935A61P35/00
Inventor 陈维汪博钟伊南王峥黄德春
Owner CHINA PHARM UNIV
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