Reversible crosslinked biodegradable polymer vesicle having positive charges on inner membrane, preparation method thereof and application in preparation of antineoplastic drugs

A technology for degrading polymers and anti-tumor drugs, applied in the field of medicine, can solve the problems of small toxic and side effects, high efficiency nanovesicles, and poor efficiency, and achieve the effects of avoiding loss and toxic side effects, efficient loading, and promoting cell proliferation

Active Publication Date: 2016-11-23
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, especially in the physiological environment, it is negatively charged, which leads to poor efficiency of its entry into cells.
[0005] However, in the existing polymer vesicle technology, there is still a lack of high-efficiency nanovesicles that are stable in vivo circulation, specifically target tumors, release drugs quickly in cells, and have low toxic and side effects, especially the lack of high-efficiency loading, very Biocompatible polymersomes for good protection

Method used

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  • Reversible crosslinked biodegradable polymer vesicle having positive charges on inner membrane, preparation method thereof and application in preparation of antineoplastic drugs
  • Reversible crosslinked biodegradable polymer vesicle having positive charges on inner membrane, preparation method thereof and application in preparation of antineoplastic drugs
  • Reversible crosslinked biodegradable polymer vesicle having positive charges on inner membrane, preparation method thereof and application in preparation of antineoplastic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1 Synthetic polymer PEG5k-P(DTC4.6k-TMC13.5k)-SP

[0078] The synthesis is divided into two steps. First, ring-opening polymerization is used to prepare PEG5k-P (DTC4.6k-TMC13.5k) diblock copolymer. The specific operation is as follows. Under nitrogen environment, MeO-PEG-OH ( M n = 5.0 kg / mol, 0.20 g, 40 μmol), TMC (0.6 g, 5.9 mmol) and DTC (0.192g, 1.0 mmol) were dissolved in dichloromethane (DCM, 6.8 mL), and the ring-opening polymerization catalyst was added rapidly, Such as zinc bis(bistrimethylsilyl)amine (7.7 mg, 20 μmol). The airtight reactor was sealed and placed under magnetic stirring in an oil bath at 40 °C for 24 hours. After terminating the reaction with glacial acetic acid, precipitate twice in glacial ether, filter with suction, and dry under vacuum at room temperature to obtain the product. Yield: 90.3%. 1 H NMR (400 MHz, DTCl 3 ): PEG: δ 3.38,3.65; TMC: δ 4.24, 2.05; DTC: δ 4.32, 3.02. According to NMR calculation, the molecular weight o...

Embodiment 2

[0082] Example 2 Synthesis of block copolymer Mal-PEG6k-P (DTC4.8k-TMC15.2k)-SP

[0083] The synthesis of Mal-PEG6k-P (DTC4.8k-TMC15.2k)-SP is similar to that of Example 1, and is also divided into two steps, except that the initiator MeO-PEG-OH in the first step is replaced by Malay Imide-functionalized Mal-PEG6k-OH, ring-opening polymerization of TMC and DTC to obtain Mal-PEG6k-P (DTC4.8k-TMC15.2k), then its terminal hydroxyl was activated with NPC, and then reacted with the primary amine of spermine be made of. The specific operation is similar to the first embodiment. Yield: 90.2%. 1H NMR (400 MHz, DTCl3): PEG: δ3.38, 3.65; TMC: δ 4.24, 2.05; DTC: δ 4.32, 3.02, and the characteristic peaks of Mal and spermine. The number-average molecular weight of the polymer was calculated as 6.0-(4.8-15.2)-0.2 kg / mol through the integral ratio of the characteristic peak area.

Embodiment 3

[0084] Example 3 Synthesis of Targeted Diblock Polymer DP8-PEG6.5k-P(DTC6k-TMC15k)

[0085] The synthesis of DP8-PEG6.5k-P(DTC6k-TMC15k) is similar to that of Example 1, which is also divided into two steps. In the first step, the initiator MeO-PEG-OH in the first step of Example 1 is replaced by NHS-PEG6.5k-OH functionalized with N-hydroxysuccinimide, and ring-opening polymerization of TMC and DTC is carried out to obtain NHS-PEG6 .5k-P(DTC6k-TMC15k), that is, add 0.15 g ( 0.781 mmol) DTC, 0.43 g of TMC, 0.2 g ( 0.0154 mmol) NHS-PEG6.5k-OH and 5 ml DCM was dissolved, and then 5.9 mg (0.0154 mmol) of a ring-opening polymerization catalyst such as bis(bistrimethylsilyl)amine zinc was added, and the subsequent treatment was the same as in Example 1. NMR calculated NHS-PEG6.5k-P (DTC6k-TMC15k) by integral area. In the second step, the polypeptide DMAPTVLP (DP8) is added according to the molar ratio of its amino group to NHS-PEG6.5k-P (DTC6k-TMC15k) 3:1, amidation reaction at 30...

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Abstract

The invention discloses a reversible crosslinked biodegradable polymer vesicle having positive charges on an inner membrane, a preparation method thereof and application in preparation of antineoplastic drugs. The biodegradable polymer vesicle based on tumor targeting of a block polymer PEG-P (TMC-DTC)-SP or PEG-P (LA-DTC)-SP, having the positively charged membrane, reversibly crosslinked in reduction sensitivity and intracellularly solvable and crosslinked can effectively support and protect biological macromolecules such as proteins, DNA and siRNA and micromolecular drugs with negative charges in a physical environment and can be delivered to intravital tumor cells to induce apoptosis. The system has lots of unique advantages including simple and easy controllability of preparation, excellent biocompatibility, excellent controlled drug release property, super-strong in-vivo circulation stability, superior cancerous cell targeting and remarkable cancer cell apoptosis capability and the like. Therefore, the reversible crosslinked biodegradable polymer vesicle is expected to become a simple, stable, multifunctional nano system platform integrating multiple advantages and is used for efficient, active and targeted delivery from nucleic acids to in-situ tumors.

Description

technical field [0001] The invention belongs to the technical field of medicines, and specifically relates to a reversible cross-linked biodegradable polymer vesicle with a positive inner membrane, a preparation method thereof, and an application in the delivery of biological medicines and negatively charged small molecule medicines in a physiological environment. Background technique [0002] Cancer is a major killer that threatens human health, and its morbidity and mortality are increasing year by year. The polymer vesicles formed by the self-assembly of amphiphilic polymers can be adjusted to be large, and can simultaneously load hydrophilic drugs and hydrophobic drugs, which is an ideal carrier for the preparation of anti-tumor nano-medicines. In particular, the water-quality inner cavity of the vesicle can provide an ideal space for biomacromolecular drugs such as protein drugs and nucleic acid drugs. However, the loading efficiency of existing vesicles for these biom...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/34A61K45/00A61P35/00C08G81/00
CPCA61K9/1273A61K45/00A61P35/00C08G81/00A61K9/127A61K47/34
Inventor 孟凤华方媛杨炜静邹艳钟志远
Owner SUZHOU UNIV
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