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Reversible cross-linked biodegradable polymer vesicle with asymmetric membrane structure and preparation method thereof

A technology for degrading polymers and membrane structures, which can be used in medical preparations containing non-active ingredients, medical preparations containing active ingredients, and drug combinations. It can solve problems such as in vivo instability, poor targeting, and high cytotoxicity. Achieve the effects of avoiding losses and toxic side effects, solving disease problems, and efficiently migrating

Active Publication Date: 2019-02-26
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that existing PEI vectors have the defects of high gene recombination and transfection efficiency but high cytotoxicity, and low cytotoxicity but poor gene recombination and transfection efficiency.
The research results of using nanocarriers such as liposomes and polyion complexes containing cations to load nucleic acids are not satisfactory. There are instability in vivo, poor targeting, low gene complex and transfection efficiency, and there are still cells. toxicity problem
Currently there is no solution that can solve these problems at the same time

Method used

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  • Reversible cross-linked biodegradable polymer vesicle with asymmetric membrane structure and preparation method thereof
  • Reversible cross-linked biodegradable polymer vesicle with asymmetric membrane structure and preparation method thereof
  • Reversible cross-linked biodegradable polymer vesicle with asymmetric membrane structure and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Synthesis of PEG5k-P(DTC4.4k-TMC19.8k)-bPEI1.8k block copolymer

[0085] The synthesis of PEG5k-P(DTC4.4k-TMC19.8k)-bPEI is divided into two steps, the first is ring-opening polymerization to prepare PEG5k-P(DTC4.4k-TMC19.8k) diblock copolymer, the specific operation is as follows, in In the nitrogen glove box, weigh MeO-PEG-OH ( M n = 5.0 kg / mol, 0.50 g, 100 μmol), TMC (2.0 g, 19.2 mmol) and DTC (0.50 g, 2.60 mmol) were dissolved in dichloromethane (DCM, 7.0 mL), and the ring-opening polymerization catalyst bis Zinc (bistrimethylsilyl)amine (29 mg, 75 μmol). The airtight reactor was sealed and placed under magnetic stirring in an oil bath at 40 °C for 2 days. 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 PEG5k-P (DTC4.4k-TMC19.8k).

[0086] Next, PEG5k-P (DTC4.4k-TMC19.8k) was activated by p-nitrophenyl hydroxychloroformate NPC, and then...

Embodiment 2

[0088] Example 2 Synthesis of Mal-PEG6k-P (DTC4.8k-TMC19.2k)-lPEI1.2k block copolymer

[0089] The synthesis of Mal-PEG6k-P(DTC4.8k-TMC19.2k)-lPEI1.2k is similar to embodiment one, also is divided into two steps, just the initiator MeO-PEG-OH in the first step wherein is changed to Maleimide-functionalized Mal-PEG6k-OH, ring-opening polymerization of TMC and DTC to obtain Mal-PEG6k-P (DTC4.8k-TMC19.2k), whose terminal hydroxyl was activated by NPC, and then combined with linear PEI (lPEI) primary amine ( M n =1.2 kg / mol) reaction. The specific operation was similar to that of Example 1, the product was precipitated twice in glacial ether, filtered with suction and dried under vacuum at room temperature to obtain the product. Yield: 93.2%. 1 H NMR (400 MHz, DTCl 3 ): PEG: δ3.38, 3.65; TMC: δ 4.24, 2.05; DTC: δ 4.32, 3.02, PEI: δ 2.56-2.98. The number average molecular weight of the polymer is calculated as 6.0-(4.8-19.2)-1.2 kg / mol through the integral ratio of the charac...

Embodiment 3

[0090] Example 3 Synthesis of cNGQ-PEG7k-P (DTC4.8k-TMC19.2k) diblock copolymer

[0091]The synthesis of cNGQ-PEG7k-P (DTC2.8k-TMC14.2k) is similar to Example 1, and it is also divided into two steps. The initiator MeO-PEG-OH in the first step is replaced by N-hydroxysuccinimide Functionalized NHS-PEG-OH, ring-opening polymerization of TMC and DTC to obtain NHS-PEG7k-P (DTC4.8k-TMC19.2k); secondly, peptide C(NGQGEQ) (cNGQ) with free primary amines combined with NHS-PEG7k -P(DTC4.8k-TMC19.2k) is bonded by amidation reaction. Briefly, NHS-PEG7k-P(DTC4.8k-TMC19.2k) (0.5 g, 0.017 mmol) and cNGQ (20 mg, 0.033 mmol) were successively dissolved in 5 mL DMF, reacted at room temperature for 2 days, and dissolved in distilled water Dialyzed for two days (MWCO 3500), freeze-dried to obtain the product cNGQ-PEG7k-P (DTC4.8k-TMC19.2k). Yield: 81.2%. 1 H NMR (400 MHz, DMSO- d 6 ): PEG: δ 3.51; TMC: δ4.23, 1.94; DTC: δ 4.13, 2.99; cNGQ: δ 6.84–7.61. The grafting rate of cNGQ measured b...

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Abstract

The invention discloses a reversible cross-linked biodegradable polymer vesicle with an asymmetric membrane structure and a preparation method thereof. Triblock polymers PEG-P(TMC-DTC)-PEI or PEG-P(DLLA-DTC)-PEI is synthesized, and a polymer vesicle with the asymmetric membrane structure is obtained by self-assembly and self-crosslinking of the triblock polymer PEG-P(TMC-DTC)-PEI or PEG-P(DLLA-DTC)-PEI, or targeted RCCPs is obtained by targeted molecule self-assemble, and the inner shell is PEI for complexing and loading of nucleic acids by electrostatic interaction; the membrane is reversiblecross-linked biodegradable well-biocompatible polyester / polycarbonate, side chain dithiolane is similar to human body's natural antioxidant lipoic acid, and the outer shell is PEG-based and can target cancer cells. Studies on vector complex functional siRNA, in-vitro and in-vivo gene silencing effect, in-vivo blood circulation and biodistribution, conditions and toxic and side effects of treatment of mice with orthotopic lung cancer find that the reversible cross-linked biodegradable polymer vesicle is expected to become a simple, stable, multi-functional nano-system platform for efficient, active targeted delivery of siRNA to tumors in situ.

Description

[0001] The present invention belongs to the invention titled reversibly cross-linked biodegradable polymer vesicles with asymmetric membrane structure and its preparation method and application in nucleic acid medicine, the application date is June 30, 2016, and the application number is 201610501766.7 patent application The divisional application belongs to the product technology part. technical field [0002] The invention belongs to the drug carrier technology, and in particular relates to a reversible cross-linked biodegradable polymer vesicle with an asymmetric membrane structure and a preparation method thereof. Background technique [0003] Gene therapy refers to the process of delivering genes with specific functions to specific tissue cells of organisms through certain methods to treat diseases. A variety of genetic diseases can be cured by using a variety of disease-causing genes that have been accurately identified to replace diseased genes in tissue cells or inhi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/59A61K48/00A61K31/713A61K9/127A61P35/00C08G81/02
CPCA61K9/1273A61K31/713A61K48/0041A61K48/0058A61K47/59C08G81/027C08G2230/00
Inventor 孟凤华邹艳杨炜静孟浩钟志远
Owner SUZHOU UNIV
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