Charge-reversal polymer micelles, drug-loaded micelles and preparation methods thereof

Abstract

The invention discloses a charge-reversal polymer micelle, a drug-loaded micelle and a preparation method thereof. The basic polyamino acid containing a protecting group and the acidic polyamino acid containing a protecting group are generated under the crosslinking action of a BACy crosslinking agent. The cross-linking reaction obtains a cross-linked polymer, which is then hydrolyzed to remove the protective groups of the basic polyamino acid and the acidic polyamino acid in the cross-linked polymer, and finally obtain a cross-linked polyamino acid composed of a positively charged polyamino acid and a negatively charged polyamino acid. Together they form charge-inversion polymer micelles with a three-dimensional network structure. The charge-inversion polymer micelles and drug-loaded micelles not only have the advantages of good structural stability, biocompatibility, and low long-term toxicity, but also have dual response characteristics of reduction responsiveness and pH responsiveness, which can realize the Long-term accumulation and high penetration of bundles in tumor cells, and improve drug release efficiency.

Description

technical field

[0001] The invention belongs to the technical field of drug carrier and its preparation, and relates to a reduction-responsive, pH-responsive polymer micelle and a drug-loaded micelle with a tumor cell microenvironment responsiveness, in particular to a charge-reversal polymer micelle And a drug-loaded micelle based on the charge-reversal polymer micelle and a preparation method thereof. Background technique

[0002] Polymer micelles are nanoparticles formed by the self-assembly of amphiphilic polymers in aqueous solution. The particle size is generally 10-200 nm. Tumor areas clustered. At the same time, polymer micelles can not only use the hydrophobic core to encapsulate drug molecules, but the hydrophilic shell can make them stably dispersed in aqueous solution. Therefore, polymer micelles are widely used in the delivery of anticancer drugs. However, to complete the delivery of drugs in vivo, polymer micelles as carriers not only need to have excellent b...

Examples

Embodiment 1

[0053] (1) Preparation of polybenzyloxycarbonyl lysine

[0054] Dissolve allylamine and benzyloxycarbonyllysine anhydride in DMF at a molar ratio of 1:15 to form a mixed solution with a total solute concentration of 0.50 g / mL, then react at 25°C for 12 hours, and then add to the reaction product Add diethyl ether for precipitation until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and dried at 60°C and 0.010MPa for 24 hours to obtain polybenzyloxycarbonyllysine.

[0055] (2) Preparation of polybenzyl glutamate

[0056] Dissolve allylamine and benzyl glutamate anhydride in DMF at a molar ratio of 1:20 to form a mixed solution with a total solute concentration of 0.50 g / mL, then react at 25°C for 12 hours, and then add Precipitate with diethyl ether until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and dried at 60°C and 0.010MPa for 24 hours to obtain polyben...

Embodiment 2

[0077] (1) Preparation of polybenzyloxycarbonyl lysine

[0078] Dissolve allylamine and benzyloxycarbonyllysine anhydride in CH at a molar ratio of 1:25 2 Cl 2 In this method, a mixed solution with a total solute concentration of 0.40g / mL was prepared, and then reacted at 30°C for 18 hours, and then added ether to the reaction product for precipitation until the precipitated product no longer increased. Dry at 60°C and 0.012MPa for 24 hours to obtain polybenzyloxycarbonyllysine.

[0079] (2) Preparation of polybenzyl glutamate

[0080] Dissolve allylamine and benzyl glutamate anhydride in CH at a molar ratio of 1:30 2 Cl 2 In this method, a mixed solution with a total solute concentration of 0.40g / mL was prepared, and then reacted at 30°C for 18 hours, and then added ether to the reaction product for precipitation until the precipitated product no longer increased. Dry at 60°C and 0.012MPa for 24 hours to obtain polybenzyl glutamate.

[0081] (3) Preparation of charge-re...

Embodiment 3

[0086] (1) Preparation of poly-tert-butoxycarbonyl lysine

[0087] Dissolve allylamine and tert-butoxycarbonyllysine cyclic anhydride in DMSO at a molar ratio of 1:35 to form a mixed solution with a total solute concentration of 0.30 g / mL, then react at 35°C for 24 hours, and then to the reaction product Diethyl ether was added to precipitate until the precipitated product no longer increased, and the obtained precipitated product was suction-filtered and dried at 60°C and 0.014MPa for 24 hours to obtain poly-tert-butoxycarbonyllysine.

[0088] (2) Preparation of poly tert-butyl glutamate

[0089] Dissolve allylamine and tert-butyl glutamate anhydride in THF at a molar ratio of 1:40 to form a mixed solution with a total solute concentration of 0.25 g / mL, then react at 25°C for 24 hours, and then add to the reaction product Add diethyl ether for precipitation until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and drie...

technical field

[0001] The invention belongs to the technical field of drug carrier and its preparation, and relates to a reduction-responsive, pH-responsive polymer micelle and a drug-loaded micelle with a tumor cell microenvironment responsiveness, in particular to a charge-reversal polymer micelle And a drug-loaded micelle based on the charge-reversal polymer micelle and a preparation method thereof. Background technique

[0002] Polymer micelles are nanoparticles formed by the self-assembly of amphiphilic polymers in aqueous solution. The particle size is generally 10-200 nm. Tumor areas clustered. At the same time, polymer micelles can not only use the hydrophobic core to encapsulate drug molecules, but the hydrophilic shell can make them stably dispersed in aqueous solution. Therefore, polymer micelles are widely used in the delivery of anticancer drugs. However, to complete the delivery of drugs in vivo, polymer micelles as carriers not only need to have excellent b...

Examples

Embodiment 1

[0053] (1) Preparation of polybenzyloxycarbonyl lysine

[0054] Dissolve allylamine and benzyloxycarbonyllysine anhydride in DMF at a molar ratio of 1:15 to form a mixed solution with a total solute concentration of 0.50 g / mL, then react at 25°C for 12 hours, and then add to the reaction product Add diethyl ether for precipitation until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and dried at 60°C and 0.010MPa for 24 hours to obtain polybenzyloxycarbonyllysine.

[0055] (2) Preparation of polybenzyl glutamate

[0056] Dissolve allylamine and benzyl glutamate anhydride in DMF at a molar ratio of 1:20 to form a mixed solution with a total solute concentration of 0.50 g / mL, then react at 25°C for 12 hours, and then add Precipitate with diethyl ether until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and dried at 60°C and 0.010MPa for 24 hours to obtain polyben...

Embodiment 2

[0077] (1) Preparation of polybenzyloxycarbonyl lysine

[0078] Dissolve allylamine and benzyloxycarbonyllysine anhydride in CH at a molar ratio of 1:25 2 Cl 2 In this method, a mixed solution with a total solute concentration of 0.40g / mL was prepared, and then reacted at 30°C for 18 hours, and then added ether to the reaction product for precipitation until the precipitated product no longer increased. Dry at 60°C and 0.012MPa for 24 hours to obtain polybenzyloxycarbonyllysine.

[0079] (2) Preparation of polybenzyl glutamate

[0080] Dissolve allylamine and benzyl glutamate anhydride in CH at a molar ratio of 1:30 2 Cl 2 In this method, a mixed solution with a total solute concentration of 0.40g / mL was prepared, and then reacted at 30°C for 18 hours, and then added ether to the reaction product for precipitation until the precipitated product no longer increased. Dry at 60°C and 0.012MPa for 24 hours to obtain polybenzyl glutamate.

[0081] (3) Preparation of charge-re...

Embodiment 3

[0086] (1) Preparation of poly-tert-butoxycarbonyl lysine

[0087] Dissolve allylamine and tert-butoxycarbonyllysine cyclic anhydride in DMSO at a molar ratio of 1:35 to form a mixed solution with a total solute concentration of 0.30 g / mL, then react at 35°C for 24 hours, and then to the reaction product Diethyl ether was added to precipitate until the precipitated product no longer increased, and the obtained precipitated product was suction-filtered and dried at 60°C and 0.014MPa for 24 hours to obtain poly-tert-butoxycarbonyllysine.

[0088] (2) Preparation of poly tert-butyl glutamate

[0089] Dissolve allylamine and tert-butyl glutamate anhydride in THF at a molar ratio of 1:40 to form a mixed solution with a total solute concentration of 0.25 g / mL, then react at 25°C for 24 hours, and then add to the reaction product Add diethyl ether for precipitation until the precipitated product no longer increases, and the resulting precipitated product is suction-filtered and drie...

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