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Preparation and application of reducing sensitive nano-micelle

A nanomicelle, sensitive technology, applied in the field of preparation and application of amphiphilic block polymers, can solve the problems of inability to release the drug and reduce the efficacy of the drug, and achieves improved bioavailability, improved stability, and is not easy to solve. away effect

Active Publication Date: 2017-05-31
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to provide a preparation and application of reduction-sensitive nanomicelles, to solve the problem that aggregates formed by self-assembly of amphiphilic copolymers, such as nanoparticles, nanomicelles, and polymer vesicle drug carriers, cannot effectively The problem of releasing the drug and reducing the efficacy of the drug

Method used

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preparation example Construction

[0038] The preparation method of nano micelles: the amphiphilic block polymer is first dissolved in an organic solvent, and the secondary water with a mass percentage of 180%-270% is added dropwise to the polymer solution under stirring at room temperature; it is formed by self-assembly Nano micelles with polyphosphate as the hydrophilic shell and polyamino acid ester as the hydrophobic core; the particle diameter of the nano micelles is 10-300nm, and the particle diameter distribution PDI is 0.01-0.30.

[0039] The polymer solution is a solution of dimethyl sulfoxide, tetrahydrofuran or N,N-dimethylformamide with a polymer mass percentage concentration of 0.2%; the organic solvent includes: dimethyl sulfoxide, tetrahydrofuran or N, N-Dimethylformamide.

[0040] The amphiphilic block polymer is a reduction-responsive polyphosphate-polyamino acid block polymer, and has a method for preparing a reductive polyphosphate-polybenzyl glutamate amphiphilic block polymer Yes: At room ...

Embodiment 1

[0065] Embodiment 1: Synthetic cyclic phosphate monomer

[0066] The cyclic phosphate monomer 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EEP) is based on phosphorus trichloride as a starting material, and ethylene glycol through nucleophilic Substitution and ring closure to form 2-chloro-1,3,2-dioxaphospholane (CP), and then react with oxygen to obtain 2-chloro-2-oxo-1,3,2-dioxaphospholane An important phosphorus oxychloride intermediate of pentane (COP). Finally, react COP with ethanol and use triethylamine (TEA) as an acid-binding agent to synthesize the cyclic phosphate monomer EEP. The specific operation is as follows:

[0067] Under nitrogen protection, 350 mL of anhydrous dichloromethane and phosphorus trichloride (412.5 g, 3 mol) were added into the flask. After stirring evenly, ethylene glycol (186.0g, 3mol) was slowly added dropwise to the system under vigorous stirring, and reacted at room temperature for 30 minutes. After the reaction was stopped, the solvent was remo...

Embodiment 2

[0070] Example 2: Synthesis of Polymer PEEP-SS-NH 2

[0071] The macromolecular initiator is based on small molecule isopropanol as an initiator, stannous octoate Sn(Oct) 2 As a catalyst, it is obtained by ring-opening polymerization of cyclic phosphate monomers to synthesize polyphosphate PEEP-OH at the hydroxyl end, and then sequentially reacting with succinic anhydride (SA) and cysteamine.

[0072] Under nitrogen protection, isopropanol (191.4mg, 3.19mmol) and EEP monomer (10g, 65.8mmol) were dissolved in 48mL of anhydrous THF, and stannous octoate (324.2mg, 0.8mmol) was added to the system at 35°C After stirring and reacting for 3 h, the system was settled in methanol / glacial ether (v / v, 1:10), and vacuum-dried at room temperature to obtain the polymer PEEP. The yield was 73.5%.

[0073] Under the protection of nitrogen, the hydroxyl-terminated polyphosphate PEEP-OH (5.5g, 1.0mmol) and succinic anhydride (0.12g, 1.2mmol) were dissolved in a mixed solution of 50mL dichlo...

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Abstract

The invention relates to preparation and application of a reducing sensitive nano-micelle, belonging to preparation and application of an amphiphilic block polymer. A hydrophilic section and a hydrophobic section of the amphiphilic block polymer are connected with each other by a reducing responsive sulfur-sulfur bond; the nano-micelle is formed by self-assembling; the reducing sensitive nano-micelle consists of a shell and an inner core, wherein the shell is a hydrophilic polymer, and the inner core is a hydrophobic polymer; the hydrophilic section of the amphiphilic block polymer is polyphosphate, the hydrophobic section of the amphiphilic block polymer is poly(benzyl glutamate), and the hydrophilic section and the hydrophobic section of the amphiphilic block polymer are connected with each other by the reducing responsive sulfur-sulfur bond. The reducing sensitive nano-micelle has the advantages that the drug-loaded nano-micelle is difficult to dissociate outside the cells or in the blood, so that the drug encapsulated in the nano-micelle is enabled to be stable; once the nano-micelle enters the cancer cell, the sulfur-sulfur bond can be disconnected by glutathione which is a reducing matter in the cell, so that the nano-micelle is rapidly dissociated, the anti-cancer drug encapsulated in the nano-micelle can be rapidly and effectively released out, and an effective treatment effect is achieved; the reducing sensitive nano-micelle overcomes the defects that the drug is easy to leak in vivo, low in transport efficiency, slow in intracellular release speed, and the like.

Description

technical field [0001] The invention relates to the preparation and application of an amphiphilic block polymer, in particular to the preparation and application of a reduction-sensitive nano-micelle. Background technique [0002] In recent decades, micelles formed by amphiphilic block polymers have attracted great interest in the field of drug delivery. Various nanocarriers have been widely developed to improve the efficacy of cancer chemotherapy, and these nanocarriers have the ability to target and control the release of anticancer drugs due to their enhanced permeability and retention (EPR) effect. Polymeric micelles based on amphiphilic block polymers are a kind of anticancer drug nanocarriers widely used in drug delivery, which have several excellent salient features, including long circulation time, good drug solubility, and tumor site passive targeting ability (Deng, et al. J. Nano Today 2012, 7, 467-480). Amphiphilic polymers can self-assemble in water to form pol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K47/34A61K31/704A61P35/00C08G69/42C08G79/04
CPCA61K9/1075A61K31/704A61K47/34C08G69/42C08G79/04
Inventor 李玉玲徐婷王赛杜百祥
Owner XUZHOU NORMAL UNIVERSITY
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