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Low-oxygen-responsive polyamino acid-PEG stereo drug-loaded micelle and preparation method thereof

A technology of polyamino acid and drug-loaded micelles, applied in the field of biomedical materials, can solve the problems of less research on polymer micelles, achieve good dispersion and solubility, reduce toxic and side effects, and reduce distribution

Active Publication Date: 2020-01-07
NANTONG UNIVERSITY
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Problems solved by technology

[0005] At present, the research on the drug loading method of physical encapsulation is relatively extensive. Polymers can self-assemble into nanocarriers in water, such as micelles, vesicles and liposomes. Polymer nanomicelles have controllable particle size and long circulation time in vivo. However, there are few studies on environment-responsive polymer micelles that respond to external environmental stimuli.

Method used

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  • Low-oxygen-responsive polyamino acid-PEG stereo drug-loaded micelle and preparation method thereof
  • Low-oxygen-responsive polyamino acid-PEG stereo drug-loaded micelle and preparation method thereof
  • Low-oxygen-responsive polyamino acid-PEG stereo drug-loaded micelle and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] according to figure 1 The synthetic route shown is the preparation of hypoxia-responsive polyamino acid-PEG stereotactic drug-loaded micelles:

[0034] Step 1: In 6ml DMF, add 0.5g 2-nitroimidazole, 0.4g dibromoneopentyl glycol and 0.8g cesium carbonate, react at 50°C for 12h, after the reaction is completed, distill and concentrate under reduced pressure, and the concentrated silica gel column layer Analyze and separate to obtain 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol;

[0035] Step 2: In 50ml DCM, add 0.5g 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol, 0.6g p-nitrobenzoyl chloride and 0.6ml triethylamine, reacted at room temperature for 12h, concentrated by distillation under reduced pressure after the reaction, the concentrate was separated by silica gel column chromatography to obtain 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl ]propane-1,3-diylbis(4-nitrophenyl)carbonate;

[0036] Step 3: In 5ml DCM, add 0.5g 2,2-bis[(2-nitro-1H-imida...

Embodiment 2

[0039] Step 1: In 5ml DMF, add 0.45g 2-nitroimidazole, 0.26g dibromoneopentyl glycol and 0.65g cesium carbonate, react at 50°C for 12h, after the reaction is completed, distill and concentrate under reduced pressure, and concentrate the silica gel column layer Analysis and separation obtained 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol;

[0040] Step 2: In 30ml DCM, add 0.32g 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol, 0.37g p-nitrobenzoyl chloride and 0.40ml triethylamine, reacted at room temperature for 12h, concentrated by distillation under reduced pressure after the reaction, the concentrate was separated by silica gel column chromatography to obtain 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl ]propane-1,3-diylbis(4-nitrophenyl)carbonate;

[0041] Step 3: In 2ml DCM, add 0.16g 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]propane-1,3-diylbis(4-nitrophenyl ) carbonate, 0.21g paclitaxel and 0.12ml N,N-diisopropylethylamine, react at room temperature f...

Embodiment 3

[0044] Step 1: In 8ml DMF, add 0.67g 2-nitroimidazole, 0.52g dibromoneopentyl glycol and 0.97g cesium carbonate, react at 50°C for 12h, after the reaction is completed, distill and concentrate under reduced pressure, and the concentrated silica gel column layer Analysis and separation obtained 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol;

[0045] Step 2: In 60ml DCM, add 0.65g 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-propanediol, 0.74g p-nitrobenzoyl chloride and 0.80ml triethylamine, reacted at room temperature for 12h, concentrated by distillation under reduced pressure after the reaction, the concentrate was separated by silica gel column chromatography to obtain 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl ]propane-1,3-diylbis(4-nitrophenyl)carbonate;

[0046] Step 3: In 8ml DCM, add 0.65g 2,2-bis[(2-nitro-1H-imidazol-1-yl)methyl]propane-1,3-diylbis(4-nitrophenyl ) carbonate, 0.85g paclitaxel and 0.25ml N,N-diisopropylethylamine, react at room temperature ...

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Abstract

The present invention discloses a low-oxygen-responsive polyamino acid-PEG stereo drug-loaded micelle and a preparation method thereof. The preparation method comprises the following steps: firstly selecting 2-nitroimidazole and dibromo neopentyl glycol to conduct reaction under catalysis of cesium carbonate to obtain 2,2-bis[(2-nitro-1H-imidazole-1-yl)methyl]-1,3-propylene glycol, then conductingacyl halide with p-nitrobenzoyl chloride in presence of triethylamine to obtain 2,2-bis[(2-nitro-1H-imidazole-1-yl)methyl]propane-1,3-diylbis(4-nitrophenyl)carbonate, then conducting reaction with paclitaxel under catalysis of N,N-diisopropylethylamine, then adding poly L-amino acid-PEG or poly D-amino acid-PEG to respectively obtain bis 2-nitroimidazole-paclitaxel-poly L amino acid-PEG and bis 2-nitroimidazole-paclitaxel-poly D amino acid-PEG, respectively, finally mixing the two materials at equal amount in a PBS buffer, conducting homogenization at high speed, and conducting extruding witha filter membrane with a pore size of 100 nm to obtain a finished product. The prepared drug-loaded micelle has high encapsulation efficiency and also low-oxygen-responsive characteristics, can be effectively accumulated in tumor tissues to achieve a very good antitumor effect, and reduces distribution of drugs in other normal tissues to reduce toxic and side effects.

Description

technical field [0001] The invention relates to hypoxia-responsive polyamino acid-PEG stereotactic drug-loaded micelles and a preparation method thereof, belonging to the field of biomedical materials. Background technique [0002] The development of nanotechnology has brought the study of pharmaceutical dosage forms into a new stage. Nano-controlled release carriers can significantly prolong drug efficacy, reduce toxicity, and improve activity and bioavailability when administered. Amphiphilic copolymers with block or graft structures can spontaneously form nanometer-sized micelles in water due to the solubility difference between hydrophilic groups and hydrophobic groups in the medium. Amphiphilic polymer micelles have shown excellent performance in drug controlled release, localized targeted release, etc., and have great application prospects. [0003] At present, block copolymers with polyethylene glycol as the hydrophilic group, polylactic acid and its copolymer with g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/337A61K47/64C08G69/48A61P35/00
CPCA61K9/1075A61K31/337A61K47/6455A61P35/00C08G69/48
Inventor 尹晓敏陆舒钱慰
Owner NANTONG UNIVERSITY
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