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Preparation and application of hyaluronic acid-antitumor 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: 2014-04-30
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-antitumor drug conjugate and composite nanoparticle composition
  • Preparation and application of hyaluronic acid-antitumor drug conjugate and composite nanoparticle composition
  • Preparation and application of hyaluronic acid-antitumor drug conjugate and composite nanoparticle composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0055] (1) Dissolve 100 mg of fluorene methoxycarbonyl-valine (Fmoc-Val) and 170 mg of paclitaxel (PTX) in dichloromethane, add 24 mg of dimethylaminopyridine (DMAP) and 46 mg of carbodiimide hydrochloride ( EDC·HCl), react in ice bath for 1 h, and stir for 8 h. The reaction solution was washed with 0.05 mol / L hydrochloric acid solution and deionized water, the organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated, added with dichloromethane solution of pyrrolidone, and stirred for 3 h. The crude product was obtained by vacuum drying. The product was purified by column chromatography to obtain 2'-Valyl-paclitaxel (2'-Val-PTX).

[0056] (2) Dissolving sodium hyaluronate in purified water, treating with cation exchange resin, and freeze-drying to obtain hyaluronic acid (HA). Dissolve 600 mg of hyaluronic acid (HA) in formamide, add 38.4 mg of carbodi...

Embodiment 2

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

[0062] (1) Dissolve 110 mg of fluorene methoxycarbonyl-methionine (Fmoc-Met) and 170 mg of paclitaxel (PTX) in dichloromethane, add 24 mg of dimethylaminopyridine (DMAP) and 46 mg of carbodiimide hydrochloride (EDC·HCl), reacted in an ice bath for 1 h, and stirred at room temperature for 8 h. The reaction solution was washed with 0.05mol / L hydrochloric acid solution and deionized water, the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, added with ethanolamine dichloromethane solution, and stirred for 4 h. Vacuum drying gave the crude product, which was purified by column chromatography to give 2'-methionyl-paclitaxel (2'-Met-PTX).

[0063] (2) Weigh cetyltrimethylammonium bromide (CTAB), dissolve it in purified water (phase A) at 40°C; take sodium hyaluronate and dissolve it in purified water (phase B) at 40°C; Add A to B, react for 2 h, filte...

Embodiment 3

[0065] Preparation of Hyaluronic Acid-Docetaxel Conjugate (HA-DTX) (Linking Arm is Leucine)

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

[0067] (2) Dissolve sodium hyaluronate in 0.1 mol / L hydrochloric acid solution, and acidify at 4°C for 15 h. Add TBA (tetrabutylammonium hydroxide) to adjust pH to 8.0, dialysis treatment for 3 days, r...

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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 present invention relates to the field of polymer chemistry, the field of pharmaceutical excipients or pharmaceutical preparations. Specifically, the invention relates to a preparation method of a hyaluronic acid-antitumor drug conjugate and a composite nanoparticle. It includes the preparation method of anti-tumor drug and linking arm, targeting ligand hyaluronic acid or its ammonium salt and anti-tumor drug-linking arm; the present invention also relates to a hyaluronic acid-anti-tumor drug conjugate 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 of 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 Applications(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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