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Preparation and application of hyaluronic acid-antineoplastic drug conjugate and composite nanoparticle composition

An anti-tumor drug, hyaluronic acid technology, applied in the field of polymer chemistry, can solve the problems of drug resistance, large toxic and side effects, poor solubility of anti-tumor drugs, etc.

Active Publication Date: 2017-02-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the difficulty in early detection and diagnosis of cancer, chemotherapy plays an important role in clinical practice, but there are still various problems and challenges, such as poor solubility of anti-tumor drugs, large toxic and side effects, and drug resistance.

Method used

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  • Preparation and application of hyaluronic acid-antineoplastic drug conjugate and composite nanoparticle composition
  • Preparation and application of hyaluronic acid-antineoplastic drug conjugate and composite nanoparticle composition
  • Preparation and application of hyaluronic acid-antineoplastic drug conjugate and composite nanoparticle composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Preparation of hyaluronic acid-paclitaxel conjugate (HA-PTX) (connecting arm is valine)

[0055] (1) Dissolve 100mg fluorenylmethoxycarbonyl-valine (Fmoc-Val) and 170mg paclitaxel (PTX) in dichloromethane, add 24mg dimethylaminopyridine (DMAP) and 46mg carbodiimide hydrochloride ( EDC·HCl), react in ice bath for 1 h, and stir for 8 h. Wash the reaction solution with 0.05 mol / L hydrochloric acid solution and deionized water, dry the organic layer with anhydrous magnesium sulfate, filter and concentrate, add pyrrolidone dichloromethane solution, and stir for 3 hours. Dry in vacuo to obtain the crude product. The product was purified by column chromatography to obtain 2'-valylpaclitaxel (2'-Val-PTX).

[0056] (2) Sodium hyaluronate was dissolved in purified water, treated with cation exchange resin, and freeze-dried to obtain hyaluronic acid (HA). Dissolve 600mg of hyaluronic acid (HA) in formamide, add 38.4mg of carbodiimide hydrochloride (EDC·HCl) and 23mg of N-hydrox...

Embodiment 2

[0061] Preparation of hyaluronic acid-paclitaxel conjugate (HA-PTX) (connecting arm is methionine)

[0062] (1) Dissolve 110mg fluorenylmethoxycarbonyl-methionine (Fmoc-Met) and 170mg paclitaxel (PTX) in dichloromethane, add 24mg dimethylaminopyridine (DMAP) and 46mg carbodiimide hydrochloride (EDC·HCl), react in ice bath for 1 h, stir at room temperature for 8 h. Wash the reaction solution with 0.05mol / L hydrochloric acid solution and deionized water, dry the organic layer with anhydrous magnesium sulfate, filter, concentrate, add ethanolamine dichloromethane solution, and stir for 4h. The crude product was obtained by vacuum drying, and the product was purified by column chromatography to obtain 2'-methionyl paclitaxel (2'-Met-PTX).

[0063] (2) Weigh cetyltrimethylammonium bromide (CTAB) and dissolve it in purified water (phase A) at 40°C; another weigh sodium hyaluronate and dissolve it in purified water (phase B); Add A to B, react for 2 hours, filter to obtain a white ...

Embodiment 3

[0065] Preparation of hyaluronic acid-docetaxel conjugate (HA-DTX) (connecting arm is leucine)

[0066] (1) Dissolve 105 mg fluorenylmethoxycarbonyl-leucine (Fmoc-Leu) and 160 mg docetaxel (DTX) in dichloromethane, add 24 mg dimethylaminopyridine (DMAP) and 46 mg carbodiimide hydrochloride Salt (EDC·HCl), react in ice bath for 1h, stir at room temperature for 8h. Wash with 0.05mol / L hydrochloric acid solution and deionized water, dry over anhydrous magnesium sulfate, filter, concentrate, add concentrated ammonia dioxane / 4M NaOH (30:9:1), and stir for 2h. Drying in vacuo gave a crude product, which was purified by column chromatography to obtain 2'-leucylpaclitaxel (2'-Leu-DTX). H NMR 1 Its structure was identified by H NMR and infrared FTIR.

[0067] (2) Sodium hyaluronate was dissolved in 0.1mol / L hydrochloric acid solution, acidified at 4°C for 15h. Add TBA (tetrabutylammonium hydroxide) to adjust the pH to 8.0, dialyze for 3 days, remove impurities, and freeze-dry to ob...

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Abstract

The present invention relates to a preparation method and an application of a hyaluronic acid-antitumor drug conjugate and composite nanoparticle composition with characteristics of active targeting antitumor effect and biodegradability. The preparation method is characterized by comprising: (1) a synthesis method for conjugating an antitumor drug and a spacer and conjugating a targeting ligand hyaluronic acid or an ammonium salt thereof and the antitumor drug-spacer; and (2) a new technology for assembling the hyaluronic acid-antitumor drug conjugate and amphiphilic polyester block copolymer composite nanoparticles. The composition has effects of substantially increased drug loading, efficacy improving, in vivo long-circulating effect achievement, active tumor targeting property and drug toxic-side effect reduction. The macromolecular conjugate and complex nanoparticle composition can be used for injection administration, oral administration or mucosal administration. In addition, the preparation method has characteristics of mature process and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of polymer chemistry, pharmaceutical auxiliary materials or pharmaceutical preparations. It specifically relates to the preparation method of hyaluronic acid-antitumor drug conjugates and composite nanoparticles. Including the coupling of anti-tumor drugs and connecting arms, the preparation method of targeting ligand hyaluronic acid or its ammonium salt and anti-tumor drugs-connecting arms; the present invention also relates to hyaluronic acid-anti-tumor drug conjugates with active target head A new technique for the assembly of nanoparticles composited with amphiphilic polyester block copolymers. Background technique [0002] Cancer has become one of the major diseases that seriously threaten human life and health. Due to the difficulty in early detection and diagnosis of cancer, chemotherapy plays an important role in clinical practice, but there are still various problems and challenges, such as poor solubility ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K45/00A61K31/704A61K31/4745A61K31/337A61K31/136A61K31/519A61K9/16A61P35/00
Inventor 李娟张瑞霞王广基
Owner CHINA PHARM UNIV
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