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Chitosan oligosaccharide fatty acid grafting-adriamycin bonded drug, preparation and applications

A technology for synthesizing doxorubicin and fatty acid, which is applied in the synthesis field of polymer prodrugs, can solve the problems of difficult uptake, difficult permeation, lack of lipophilicity of chitosan oligosaccharide, etc., and achieves the effect of solving targeted distribution and reducing toxicity

Inactive Publication Date: 2009-10-28
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, oligochitosan lacks lipophilicity and is not easily absorbed by cells, that is, it is difficult to penetrate the cell membrane.

Method used

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  • Chitosan oligosaccharide fatty acid grafting-adriamycin bonded drug, preparation and applications
  • Chitosan oligosaccharide fatty acid grafting-adriamycin bonded drug, preparation and applications
  • Chitosan oligosaccharide fatty acid grafting-adriamycin bonded drug, preparation and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) Preparation of low molecular weight chitosan (chitooligosaccharide)

[0024] Get 50 g of chitosan (95% degree of deacetylation) with a commercially available molecular weight of 450 kDa, add it to 1500 mL of 1.2% (v / v) hydrochloric acid aqueous solution, and stir for 2 hours at 55 ° C to fully dissolve the chitosan. After swelling, slowly add 2% chitosanase (w / w) solution, and perform chitosan enzymolysis reaction at a temperature of 55°C. The degradation degree of chitosan was controlled by gel permeation chromatography. After the reaction is finished, stir at 80° C. for 0.5 h, and add 0.3% (w / v) activated carbon. After diluting the reaction solution, filter it with a Buchner funnel, treat the filtrate with a 0.45 μm microporous membrane, and spray-dry to obtain chitosan oligosaccharide. After determination, the weight average molecular weight of the obtained chitosan oligosaccharide was 18.1 kDa.

[0025] (2) Synthesis of oligochitosan stearic acid graft

[00...

Embodiment 2

[0047] (1) The preparation method of low molecular weight chitosan (chitooligosaccharide)

[0048] Get 50 g of chitosan (95% degree of deacetylation) with a commercially available molecular weight of 450 kDa, add it to 1500 mL of 1.2% (v / v) hydrochloric acid aqueous solution, and stir for 2 hours at 55 ° C to fully dissolve the chitosan. After swelling, slowly add 2% chitosanase (w / w) solution, and perform chitosan enzymolysis reaction at a temperature of 55°C. The degradation degree of chitosan was controlled by gel permeation chromatography. After the reaction is finished, stir at 80° C. for 0.5 h, and add 0.3% (w / v) activated carbon. After diluting the reaction solution, filter it with a Buchner funnel, treat the filtrate with a 0.45 μm microporous membrane, and spray-dry to obtain chitosan oligosaccharide. After determination, the weight average molecular weight of the obtained chitosan oligosaccharide was 18.1 kDa.

[0049] (2) Synthesis of oligochitosan stearic acid g...

Embodiment 3

[0061] (1) The preparation method of low molecular weight chitosan (chitooligosaccharide)

[0062] Get 50 g of chitosan (95% degree of deacetylation) with a commercially available molecular weight of 450 kDa, add it to 1500 mL of 1.2% (v / v) hydrochloric acid aqueous solution, and stir for 2 hours at 55 ° C to fully dissolve the chitosan. After swelling, slowly add 2% chitosanase (w / w) solution, and perform chitosan enzymolysis reaction at a temperature of 55°C. The degradation degree of chitosan was controlled by gel permeation chromatography. After the reaction is finished, stir at 80° C. for 0.5 h, and add 0.3% (w / v) activated carbon. After diluting the reaction solution, filter it with a Buchner funnel, treat the filtrate with a 0.45 μm microporous membrane, and spray-dry to obtain chitosan oligosaccharide. After determination, the weight average molecular weight of the obtained chitosan oligosaccharide was 18.1 kDa.

[0063] (2) Synthesis of oligochitosan stearic acid g...

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Abstract

The invention provides a chitosan oligosaccharide fatty acid grafting-adriamycin bonded pro-drug, which is prepared by the following steps of: dissolving doxorubicin hydrochloride into dimethyl sulfoxide, adding ethylamine to stir and dissolving the product into naphthyridine; then dissolving cis-aconitic acid anhydride into oxetone and dropping into adriamycin solution, stirring, extracting, and centrifugating to disperse the deposits into water, freezing and drying to obtain an adriamycin- cis-aconitic acid midbody; dissolving chitosan oligosaccharide fatty acid grafting into water, additionally taking the theadriamycin-cis-aconitic acid midbody and dripping the dimethyl sulfoxide liquid, dropping into the grafting agueous solution, stirring, dialyzing, freezing and drying, thus obtaining the chitosan oligosaccharide fatty acid grafting-adriamycin bonded pro-drug; wherein the molecular weight of chitosan oligosaccharide is between 1 and 200 kDa; the deacetylation is between 70 and 100 percent; the carbon chain length of the fatty acid is between C12 and C22; and the substitution degree of the amino group is between 1 and 50 percent. The adriamycin after bonded with the chitosan oligosaccharide fatty acid grafting has remarkable antitumor curative property, can reverse the drug tolerance of tumor cells and can be applied for preparing the antitumor drugs and the drugs which can reverse the drug tolerance of tumor cells.

Description

technical field [0001] The invention belongs to the field of synthesis of polymer prodrugs, and relates to the chemical bonding of chitosan oligosaccharide-fatty acid graft and antitumor drug doxorubicin, and the synthesized chitosan-fatty acid graft bonded doxorubicin drug Application in preparing anti-tumor and reversing drug resistance of tumor cells. Background technique [0002] Malignant tumor is a major disease that seriously threatens human life. Doxorubicin is an anthracycline antineoplastic drug commonly used in clinical practice. It can be embedded in DNA, prevent RNA transcription, inhibit RNA synthesis, and prevent DNA replication. Doxorubicin has a broad antitumor spectrum and high curative effect, and is mainly used for malignant lymphosarcoma, breast cancer, ovarian cancer, small cell lung cancer, gastric cancer, liver cancer and bladder cancer. However, small molecule drugs are easily absorbed by the body, widely distributed in the body, and lack specifici...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704A61P35/00A61K47/54
Inventor 胡富强杜永忠袁弘
Owner ZHEJIANG UNIV
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