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Reversibly crosslinked biodegradable polymersome with asymmetric membrane structure as well as preparation method and application thereof to nucleic acid medicines

A technology for degrading polymers and membrane structures, which can be used in medical preparations without active ingredients, medical preparations containing active ingredients, and drug combinations, etc. It can solve the problems of instability in the body, poor targeting, and high cytotoxicity. Achieve the effect of avoiding losses and toxic side effects, solving disease problems, and efficient migration

Active Publication Date: 2016-12-07
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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  • Reversibly crosslinked biodegradable polymersome with asymmetric membrane structure as well as preparation method and application thereof to nucleic acid medicines
  • Reversibly crosslinked biodegradable polymersome with asymmetric membrane structure as well as preparation method and application thereof to nucleic acid medicines
  • Reversibly crosslinked biodegradable polymersome with asymmetric membrane structure as well as preparation method and application thereof to nucleic acid medicines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1 Synthesis of PEG5k-P(DTC4.4k-TMC19.8k)-bPEI1.8k block copolymer

[0084] 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).

[0085] Next, PEG5k-P (DTC4.4k-TMC19.8k) was activated by p-nitrophenyl hydroxychloroformate NPC, and then...

Embodiment 2

[0087] Example 2 Synthesis of Mal-PEG6k-P (DTC4.8k-TMC19.2k)-lPEI1.2k block copolymer

[0088] 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

[0089] Example 3 Synthesis of cNGQ-PEG7k-P (DTC4.8k-TMC19.2k) diblock copolymer

[0090]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 reversibly crosslinked biodegradable polymersome with an asymmetric membrane structure as well as a preparation method and application thereof to nucleic acid medicines. The polymersome and the preparation method have the advantages that a triblock polymer PEG-P(TMC-DTC)-PEI or PEG-P(DLLA-DTC)-PEI is synthesized and is self-assembled and self-crosslinked to obtain the polymersome with the asymmetric membrane structure or the triblock polymer is linked with a targeting molecule and is self-assembled to obtain targeting RCCPs; the inner shell of the polymersome is PEI and is used for compounding and loading nucleic acid through electrostatic interaction; a membrane is reversibly crosslinked biodegradable polyester / polycarbonate with good biocompatibility; dithiolane of a side chain is similar to a human body natural antioxidant lipoic acid; the outer shell of the polymersome takes PEG as the background and can target cancer cells; by studying that the carrier is compounded with functional siRNA and studying the gene silencing effects in vitro and vivo, in vivo blood circulation and bio-distribution, the condition of treating lung cancer in situ bearing mice and toxic and side effects of the polymersome, the polymersome is expected to become a nanosystem platform integrating the advantages of simplicity, stability, multifunction, and the like and is used for carrying out efficient and active targeting delivery on siRNA to tumors in situ.

Description

technical field [0001] The invention belongs to the drug carrier technology, and specifically relates to a reversibly cross-linked biodegradable polymer vesicle with an asymmetric membrane structure, a preparation method thereof, and an application in nucleic acid drug delivery. Background technique [0002] 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 inhibit the expression of diseased genes; it is also possible to promote the synthesis and regulation of intracellular proteins by delivering functional genes Toxic protein or prodrug activating enzyme synthesis for the treatment of non-genetic diseases. However, gene drugs are easily degraded by nucleases in serum, and have poor ability to ente...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K48/00A61K31/713A61K9/127A61P35/00C08G81/02
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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