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PH and Redox dual-response amphiphilic block copolymer as well as preparation method and application thereof

An amphiphilic copolymer and dual-response technology, which can be used in pharmaceutical formulations, medical preparations of non-active ingredients, emulsion delivery, etc. It can solve the problems of drug release due to micellar structure damage and large damage to organisms

Active Publication Date: 2017-01-04
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the conventional copolymers poly(ethylene imine) (PEI) used in basic research are mostly refractory materials, which are more harmful to organisms, while Poly(β-amino esters) (PAE) has good biocompatibility , can be degraded, and can be protonated from insoluble to soluble in an acidic environment, with excellent performance
[0007] However, so far, few literatures and patents have reported that PAE-based pH and Redox dual-responsive amphiphilic block copolymers can simultaneously achieve long-term circulation of drug-loaded micelles in blood, accumulation in cancer tissues, and Increased cancer cell uptake and efficient drug release due to disruption of micellar structure in response to the internal environment of cancer cells

Method used

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  • PH and Redox dual-response amphiphilic block copolymer as well as preparation method and application thereof
  • PH and Redox dual-response amphiphilic block copolymer as well as preparation method and application thereof
  • PH and Redox dual-response amphiphilic block copolymer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1: Preparation of pH and Redox double responsive amphiphilic copolymer MPEG-Linker-PAE-ss-PLGA

[0103] (1) Preparation of pH-responsive hydrophilic macromer MPEG-Linker: under inert gas protection and anhydrous conditions, solvent DCM (20mL), catalyst DCC (41mg, 0.2mmol), DMAP (4.88mg, 0.04mmol), monomer MPEG (80mg, 0.02mmol), and small molecule monomer FA (45mg, 0.3mmol) were added to a 100mL round bottom flask, and under stirring conditions, at room temperature, after 24 hours of reaction, the reaction solution was filtered. Remove the precipitate therein, collect the filtrate and concentrate it by rotary evaporation and slowly add it to 10 times (volume ratio) of cold isopropanol, place it in the refrigerator for 2h, collect the precipitate, wash the precipitate with isopropanol and diethyl ether, and obtain a solid. ℃, 35mbar and vacuum drying for 48h to obtain the aldehyde-terminated macromonomer MPEG-CHO, and the DMSO solution (20mL) of MPEG-CHO (41.32mg,...

Embodiment 2

[0109] Example 2: Preparation of pH and Redox double responsive amphiphilic copolymer MPEG-Linker-PAE-ss-PLGA

[0110] (1) Preparation of pH-responsive hydrophilic macromer MPEG-Linker: under inert gas protection and anhydrous conditions, solvent DCM (30mL), catalyst DCC (51.25mg, 0.25mmol), DMAP (30.5mg , 0.25mmol), monomer MPEG (40mg, 0.01mmol), and small molecule monomer FA (75mg, 0.5mmol) were added to a 100mL round-bottomed flask, and the reaction solution was filtered under stirring at room temperature for 24 hours. , remove the precipitate therein, collect the filtrate and slowly add it to 10 times (volume ratio) of cold isopropanol after being concentrated by rotary evaporation, place it in the refrigerator for 2h, collect the precipitate, wash the precipitate with isopropanol and diethyl ether, and obtain a solid. Vacuum-dried at 35°C and 35mbar for 48h to obtain the aldehyde-terminated macromer MPEG-CHO. MPEG-CHO (41.32mg, 0.01mmol) and DAP (1.67mL, 0.02mmol) in DMSO...

Embodiment 3

[0112] (3) Preparation of pH- and Redox-responsive amphiphilic copolymers: put a stir bar in a 50mL dry eggplant-shaped bottle, seal it with a reverse rubber stopper, freeze-vacuumize-nitrogen three times, and inject 15mL of it with a syringe in turn. Anhydrous chloroform solution of MPEG-Linker (0.838g, 0.2mmol), PLGA-Cys (0.636g, 0.2mmol) and AP (45.6μL, 0.6mmol) was added to the reaction bottle, and then 5mL of HDD (246.4 μL, 1.1mmol) of anhydrous chloroform solution was slowly added dropwise to the reaction flask, in a nitrogen atmosphere, stirred at 65°C, and reacted for 72h. After cooling the reaction solution to room temperature, slowly added to 10 times the amount (volume ratio) of cold n-hexane The precipitate was precipitated in alkanes, and the precipitate was vacuum-dried at 35°C and 35mbar for 48h to obtain an amphiphilic copolymer based on PAE's pH and Redox dual response, with a yield of 72%, Mn=39870, and Mw / Mn=1.37. Example 3: Preparation of pH and Redox doubl...

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Abstract

The invention provides a pH and Redox dual-response amphiphilic block copolymer as well as a preparation method and application thereof. The molecular formula of the copolymer provided by the invention is MPEG-Linker-PAE-ss-PLGA and the copolymer has a structure as shown in the formula I and can be prepared through the following steps of performing reaction to modify macromonomer methoxypolyethylene glycols (MPEG), thereby obtaining hydrophilic macromonomer (MPEG-Linker) with pH responsiveness; performing reaction to modify macromonomer polylactic acid-poly lactic-co-glycolic acid (PLGA) by use of disulfide bonds, thereby obtaining a hydrophobic macromonomer (PLGA-Cys) with Redox responsiveness; and performing michael addition reaction through a one-step method so as to obtain the copolymer. The copolymer provided by the invention can be used in systems for loading water-insoluble drug micelle, is capable of controlling slow release of loaded drugs in normal tissues, is low in release amount accumulated for a long time, and can be enriched and rapidly released in focus tissues, thereby improving the bioavailability and treatment effect of the medicaments.

Description

technical field [0001] The invention belongs to the technical field of polymer copolymer materials for biomedicine, and in particular relates to a pH- and Redox dual-response amphiphilic block copolymer and its preparation method and application. Background technique [0002] Nowadays, cancer has become the first cause of death of human diseases, and the morbidity and mortality are still rising, posing a huge threat to human health. According to statistics, more than 2.8 million people died of cancer in China in 2015, an average of 7,500 people per day. Cancer has increasingly become the main killer of human life and health. [0003] The treatment of cancer includes chemotherapy, radiotherapy and surgery, among which chemotherapy is the most important and effective treatment in clinical practice. The hydrophobic small molecule chemotherapeutic drugs used clinically, such as doxorubicin, camptothecin, paclitaxel, etc., have poor water solubility, cannot carry out stable long...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/34C08G81/00C08G73/00
CPCA61K9/107A61K47/10A61K47/34C08G73/00C08G81/00
Inventor 陈春英张灿阳徐梦真吴军光
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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