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Triblock polycation, and preparation method and application thereof

A polycationic, tri-block technology, applied in the field of medicine and chemical industry, can solve the problems of rapid dissociation and release of entrapped drugs, limited application range and effect, lack of selectivity, etc.

Active Publication Date: 2013-10-09
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned carriers lack selectivity to different environments inside and outside the cell. When used for the co-delivery of hydrophobic drugs and RNA drugs, it is difficult to meet the requirements of stable extracellular existence, rapid intracellular dissociation and release of the entrapped drug. and use are severely limited

Method used

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  • Triblock polycation, and preparation method and application thereof
  • Triblock polycation, and preparation method and application thereof
  • Triblock polycation, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of polyethylene glycol initiator

[0045] Weigh 15.0 g of methoxy-terminated polyethylene glycol 2000 (mPEG 2k -OH) was dissolved in 187.5 ml of dichloromethane, and 0.825 ml of triethylamine was added to the solution. Take 1.5 ml of 2-bromoisobutyryl bromide and dissolve it in 45 ml of dichloromethane, and add the 2-bromoisobutyryl bromide solution dropwise to mPEG under ice-cooling 2k -OH solution. After the dropwise addition, the reaction was continued for 48 hours, washed twice with saturated sodium bicarbonate and saturated saline, the organic phase was collected, dried overnight with anhydrous magnesium sulfate, filtered to remove magnesium sulfate, concentrated by rotary evaporation, and precipitated with diethyl ether twice to obtain acyl Bromine-modified polyethylene glycol polymer product 11.0 grams, yield 73.3%.

Embodiment 2

[0046] Embodiment 2: Preparation of polyethylene glycol-polyglycidyl methacrylate diblock copolymer

[0047] Get the macromolecular initiator (mPEG) of polyethylene glycol 2000 prepared in embodiment 1 2k -Br) 1.0 g was dissolved in 3.6 ml of N,N-dimethylacetamide (DMAC), 0.4 ml of isopropanol was added, stirred and mixed, and 1.05 ml of glycidyl methacrylate (GC) was added, pentamethyl Diethylenetriamine 42 µl. After deoxygenation in vacuum, 4.8 mg of cuprous chloride catalyst was added and reacted at 40°C for 15 hours. After the reaction was completed, it was purified with an alumina column, concentrated by rotary evaporation, precipitated with ether, and dried with a vacuum pump to obtain 1.44 g of the product, with a yield of 72%. Using deuterated chloroform as a solvent, the polymer structure was determined by H NMR spectroscopy as methoxy-terminated polyethylene glycol-polyglycidyl methacrylate (mPEG 2k -b-PGC 40 ).

Embodiment 3

[0048] Embodiment 3: Preparation of polyethylene glycol-polyglycidyl methacrylate-polydiisopropylaminoethyl methacrylate triblock copolymer

[0049] Get the methoxy-terminated polyethylene glycol-polyglycidylmethacrylate (mPEG) prepared in Example 2 2k -b-PGC 40 ) 0.2 g was dissolved in 0.3 ml of DMAC, 0.2 ml of isopropanol was added, stirred and mixed, and then 0.47 ml of diisopropylaminoethyl methacrylate monomer and 7.5 μl of pentamethyldiethylenetriamine were added. After deoxygenation, 5.0 mg of cuprous bromide catalyst was added, and reacted at 40°C for 48 hours. After the reaction was completed, the copper salt was removed through an aluminum oxide column, concentrated by rotary evaporation at 40°C, precipitated with ether, and dried in vacuum to obtain 2.0 g of the product, with a yield of 98%. Using deuterated chloroform as a solvent, the polymer structure was confirmed by hydrogen nuclear magnetic resonance as polyethylene glycol-polyglycidyl methacrylate-polydiiso...

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Abstract

The invention discloses a polyethylene glycol-aminated poly(glycidyl methacrylate)-poly(diisopropylaminoethanol methacrylate) triblock polycation and a synthetic method thereof, and a dual acid-sensitivity multilayer cation micelle prepared from the triblock polycation and a preparation method thereof. The cation micelle comprises a neutral polyethylene glycol PEG external layer, an aminated poly(glycidyl methacrylate) PAG intermediate layer and a poly(diisopropylaminoethanol methacrylate) PDPA inner layer, wherein the PEG external layer can shield a part of positive charges and improve stability of the micelle, the PAG intermediate layer has positive electricity and can absorb electronegative nucleic acid drugs, and the PDPA inner layer has hydrophobicity and can entrap hydrophobic drugs. Furthermore, the invention also discloses application of the dual acid-sensitivity multilayer cation micelle in synchronous co-delivery of nucleic acid and hydrophobic anticancer drugs, and the dual acid-sensitivity multilayer cation micelle is mainly used for reversion of multidrug resistance of cancer cells or inhibition of cancer cell metastasis.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and specifically relates to a polyethylene glycol-aminated polyglycidyl methacrylate-polydiisopropylaminoethyl methacrylate triblock polycation and a synthesis method thereof, and The multi-layer cationic micelles with double acid sensitivity prepared by the above-mentioned tri-block polycations and the preparation method. The present invention also relates to the application of the double-acid-sensitive multilayer cationic micelles for synchronous co-delivery of nucleic acid and hydrophobic anticancer drugs, mainly for reversing multidrug resistance of cancer cells or inhibiting cancer cell metastasis. Background technique [0002] Malignant tumor (cancer) has the characteristics of low cure rate, high recurrence rate and high mortality rate, and has become one of the major diseases threatening human health. According to the statistics of my country's cancer annual report...

Claims

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Application Information

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IPC IPC(8): C08F293/00C08F220/32C08F220/34C08F8/32C08G65/48A61K9/51A61K47/32
Inventor 于海军李亚平陈宪智张志文
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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