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A hypoxia-responsive polyamino acid-peg stereotactic drug-loaded micelle and its preparation method

A technology of polyamino acid and drug-loaded micelles, which is applied in the direction of pharmaceutical formulations, drug combinations, anti-tumor drugs, etc., can solve the problems of less research on polymer micelles, achieve good dispersion and solubility, reduce distribution, and reduce toxic and side effects Effect

Active Publication Date: 2021-09-28
NANTONG UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A hypoxia-responsive polyamino acid-peg stereotactic drug-loaded micelle and its preparation method
  • A hypoxia-responsive polyamino acid-peg stereotactic drug-loaded micelle and its preparation method
  • A hypoxia-responsive polyamino acid-peg stereotactic drug-loaded micelle and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] according to figure 1 The synthetic route shown below prepares 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-imidazol-1-y...

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 invention discloses a hypoxia-responsive polyamino acid-PEG stereotactic drug-loaded micelle and a preparation method thereof. The preferred method is to obtain 2,2-bis [(2‑nitro‑1H‑imidazol‑1‑yl)methyl]‑1,3‑propanediol, and then acid halide with p-nitrobenzoyl chloride in the presence of triethylamine to obtain 2,2‑bis[( 2‑nitro‑1H‑imidazol‑1‑yl)methyl]propane‑1,3‑diylbis(4‑nitrophenyl) carbonate, and paclitaxel in N,N‑diisopropylethylamine Catalyzed reaction, then add poly L-amino acid-PEG or poly D-amino acid-PEG, respectively to obtain double 2-nitroimidazole-paclitaxel-poly L-amino acid-PEG, and double 2-nitroimidazole-paclitaxel-poly D Amino acid-PEG, the last two are mixed in equal amounts in PBS buffer, homogenized at high speed, and extruded through a filter membrane with a pore size of 100nm. The drug-loaded micelles prepared by the invention have high encapsulation efficiency and low-oxygen response characteristics, can effectively accumulate in tumor tissues to achieve good anti-tumor effects, and reduce drug distribution 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 Patents(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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