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Environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle as well as preparation method and application thereof

A technology of hyaluronic acid and podophyllotoxin, which can be used in pharmaceutical formulations, antineoplastic drugs, drug combinations, etc., can solve problems such as poor water solubility, toxic side effects, and non-specific accumulation, and achieve good blood compatibility and broad application prospects , good anti-tumor effect

Pending Publication Date: 2021-12-07
DALIAN NATIONALITIES UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the disadvantages of poor water solubility, non-specific accumulation and release, and serious side effects of the current chemotherapeutic drug podophyllotoxin, the present invention provides an environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle (HA-NH-CO-PPT or HA-S-S-PPT) and its preparation method and application

Method used

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  • Environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle as well as preparation method and application thereof
  • Environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle as well as preparation method and application thereof
  • Environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] (1) HA-NH 2 Preparation: Hyaluronic acid (HA, 400 mg, equivalent to 1054 μmol of COOH groups) with a molecular weight of 3000-10000 Da, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were dissolved in a PBS solution (5 mL) with a pH of 8.0 at a molar ratio of 1:1:1, and reacted in an ice bath for 1 hour to activate the carboxyl group of HA to obtain a solution 1. Then, ethylenediamine and HA in an equimolar amount were dissolved in 5 mL of dimethyl sulfoxide (DMSO) and added to the above solution 1, and reacted at 25° C. for 24 hours. After the reaction, the resulting mixture was dialyzed against deionized water (MWCO 2000) for 72 hours, and the deionized water was changed every 6 hours. Finally, the solution was filtered and lyophilized to obtain HA-NH 2 .

[0053] (2) Preparation of PPT-COOH: Dissolve succinic anhydride (SA, 1.5mmol), podophyllotoxin (PPT) and 4-dimethylaminopyridine (DMAP) in a molar ratio of 15:1...

Embodiment 2

[0057] (1) HA-NH 2 Preparation: Hyaluronic acid (HA, 400 mg, equivalent to 1054 μmol of COOH groups) with a molecular weight of 3000-10000 Da, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were dissolved in a PBS solution (5 mL) with a pH of 8.0 at a molar ratio of 1:1:1, and reacted in an ice bath for 1 hour to activate the carboxyl group of HA to obtain a solution 1. Then, ethylenediamine and HA in an equimolar amount were dissolved in 5 mL of dimethyl sulfoxide (DMSO) and added to the above solution 1, and reacted at 25° C. for 24 hours. After the reaction, the resulting mixture was dialyzed against deionized water (MWCO 2000) for 72 hours, and the deionized water was changed every 6 hours. Finally, the solution was filtered and lyophilized to obtain HA-NH 2 .

[0058] (2) Preparation of PPT-COOH: Dissolve succinic anhydride (SA, 1.5mmol), podophyllotoxin (PPT) and 4-dimethylaminopyridine (DMAP) in a molar ratio of 15:1...

Embodiment 3

[0062] (1) HA-NH 2 Preparation: Hyaluronic acid (HA, 400 mg, equivalent to 1054 μmol of COOH groups) with a molecular weight of 3000-10000 Da, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) were dissolved in a PBS solution (5 mL) with a pH of 8.0 at a molar ratio of 1:1:1, and reacted in an ice bath for 1 hour to activate the carboxyl group of HA to obtain a solution 1. Then, ethylenediamine and HA in an equimolar amount were dissolved in 5 mL of dimethyl sulfoxide (DMSO) and added to the above solution 1, and reacted at 25° C. for 24 hours. After the reaction, the resulting mixture was dialyzed against deionized water (MWCO 2000) for 72 hours, and the deionized water was changed every 6 hours. Finally, the solution was filtered and lyophilized to obtain HA-NH 2 .

[0063] (2) Preparation of PPT-COOH: Dissolve succinic anhydride (SA, 1.5mmol), podophyllotoxin (PPT) and 4-dimethylaminopyridine (DMAP) in a molar ratio of 15:1...

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Abstract

The invention discloses an environmental response type hyaluronic acid-podophyllotoxin prodrug micelle as well as a preparation method and application thereof. The environmental response type hyaluronic acid-podophyllotoxin prodrug micelle comprises a pH-sensitive prodrug micelle and a pH and reduction dual-sensitive prodrug micelle. The preparation method comprises the following steps: starting from hyaluronic acid and podophyllotoxin as raw materials, firstly modifying the hyaluronic acid by using ethylenediamine or cystamine to synthesize aminated hyaluronic acid, then performing carboxylation treatment on the podophyllotoxin by using succinic anhydride, and finally performing condensation reaction on the aminated hyaluronic acid and the carboxylated podophyllotoxin to obtain the polymer prodrug. The synthesized prodrug can be self-assembled in an aqueous solution to form micelles, has good blood compatibility and is suitable for intravenous injection. The invention also provides an application of the prodrug micelle in drug delivery, and the prodrug micelle has controllable drug release behavior, tumor cell targeting capability and good anti-tumor effect, and has wide application prospect.

Description

technical field [0001] The invention discloses an environment-responsive hyaluronic acid-podophyllotoxin prodrug micelle, a preparation method and an application thereof, and belongs to the technical field of novel hyaluronic acid nano drug carriers. Background technique [0002] Cancer has become one of the major diseases that seriously endanger human health, with high morbidity and mortality. Chemotherapy is still the most widely used treatment. However, while the existing anti-tumor drugs have a strong killing effect on tumor cells, they will also cause serious damage to normal cells and cause multiple complications, which limits the clinical application and development of anti-tumor drugs. At present, nanoparticle drug delivery vehicles have made great progress in cancer therapy, especially polymer prodrug micelles. These polymeric prodrug micelles can passively accumulate in tumor tissues with high stability and prolonged blood circulation time. However, nonspecific ...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/61A61K31/365A61P35/00C08B37/08
CPCA61K47/6907A61K47/61A61K31/365A61P35/00C08B37/0072
Inventor 张树彪李敏赵轶男孙姣林可心刘占彪
Owner DALIAN NATIONALITIES UNIVERSITY
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