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Preparation and application of amphiphilic polysaccharide derivative carrier targeting tumor neovascularization and its pharmaceutical composition

A tumor neovascularization and amphiphilic polysaccharide technology, which can be used in drug combinations, antitumor drugs, non-active components of polymer compounds, etc., can solve side effects, low drug uptake, and poor tumor blood vessel targeting question

Active Publication Date: 2017-12-26
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First of all, the tumor blood vessel targeting of the drug is not strong. While acting on tumor blood vessels, it will also have an effect on normal tissues and cells, resulting in serious side effects
Secondly, the drug uptake rate of tumor vascular endothelial cells is low, and the effective therapeutic concentration cannot be maintained locally in tumor blood vessels.

Method used

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  • Preparation and application of amphiphilic polysaccharide derivative carrier targeting tumor neovascularization and its pharmaceutical composition
  • Preparation and application of amphiphilic polysaccharide derivative carrier targeting tumor neovascularization and its pharmaceutical composition
  • Preparation and application of amphiphilic polysaccharide derivative carrier targeting tumor neovascularization and its pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of Esbp-disulfide-acetylated hyaluronic acid

[0063] 0.1mmol of hyaluronic acid, 1mmol of 2-aminoethanethiol, 1mmol of EDC and 1mmol of NHS were dissolved in formamide. After 24 hours of reaction, the hyaluronic acid intermediate was precipitated with acetone, filtered and dialyzed with distilled water for 72 hours (MWCO=3500), frozen Dry to obtain the hyaluronic acid intermediate of free one end mercapto group.

[0064] Dissolve 0.4mmol Esbp peptide and 0.1mmol hyaluronic acid intermediate in formamide, oxidize in natural air, and react for 24h. After the reaction was completed, it was dialyzed with excess distilled water for 72 hours (MWCO=3500), and freeze-dried to obtain the Esbp-disulfide-acetylated hyaluronic acid derivative carrier.

Embodiment 2

[0065] Embodiment 2: Preparation of Esbp-disulfide-propionylated chitosan

[0066] 0.1mmol chitosan was dissolved in a mixed solvent of water and methanol (v / v=1:1), 1mmol 3-mercaptopropionic acid, 0.5mmol EDC and 0.5mmol HOBt were added, reacted for 8h, methanol was removed by rotary evaporation, and distilled water was dialyzed for 72h (MWCO= 3500), freeze-dried to obtain the chitosan intermediate of a free end sulfhydryl.

[0067] 0.5mmol Esbp peptide and 0.1mmol chitosan intermediate were dissolved in a mixed solvent of water and methanol (v / v=1:1), ammonia water was used to adjust the pH value to 8.0, potassium ferricyanide (0.2mmol) aqueous solution was added dropwise, Reaction at room temperature for 2h. After the reaction was completed, the methanol was removed by rotary evaporation, dialyzed in distilled water for 72 hours (MWCO=3500), and freeze-dried to obtain the Esbp-disulfide-propionylated chitosan derivative carrier.

Embodiment 3

[0068] Example 3: Preparation of Esbp-disulfide-acetylated chondroitin sulfate

[0069] 0.1mmol of chondroitin sulfate, 1mmol of 2-aminoethanethiol, 0.5mmol of EDC and 0.5mmol of DMAP were dissolved in formamide, and after 12 hours of reaction, the chondroitin sulfate intermediate was precipitated with acetone, suction filtered and dialyzed with distilled water for 72 hours (MWCO=3500 ), freeze-dry to obtain the chondroitin sulfate intermediate of free one-end sulfhydryl.

[0070] Dissolve 0.2mmol Esbp and 0.1mmol chondroitin sulfate intermediate in a mixed solvent of N,N-dimethylformamide and water, add iodine solution (0.2mmol) dropwise for oxidation, and react for 30min. After the reaction, use excess acetone to precipitate, filter and vacuum dry to obtain the Esbp-disulfide-acetylated chondroitin sulfate derivative carrier.

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Abstract

The invention relates to an amphipathic polysaccharide derivative carrier targeting tumor neovascularization. This kind of derivatives is to couple the polysaccharide backbone with the functional polypeptide targeting E-selectin through disulfide bonds, so that the polysaccharide has amphipathic properties, and then assembled into Nanoparticles targeting tumor neovascularization. With the help of the functional polypeptide targeting E-selectin and the high affinity of E-selectin on the surface of tumor neovascularization, the nanoparticle actively targets and delivers the drug to tumor neovascularization, and then the disulfide bonded arm can be used by the tumor The strong reducing environment-specific degradation in neovascular endothelial cells leads to the separation of functional peptides and polysaccharides targeting E-selectin, and the rapid release of drugs to therapeutic targets, which can significantly increase the concentration of free drugs in tumor neovascularization sites and enhance anti-tumor curative effect. The auxiliary material can be used as a carrier of water-insoluble or poorly soluble or amphiphilic antitumor drugs and tumor neovascularization inhibitors for intravascular injection, intramuscular injection, oral or external administration. The preparation method of the invention is simple, the process is mature, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to an amphiphilic polysaccharide derivative targeting neovascularization of tumors as a drug carrier, and also relates to a preparation method and application of the carrier. Background technique [0002] Malignant tumors are an important disease that endangers human health in the world. Although the understanding of tumor cell biology and genetics has reached the level of molecular biology, and new treatment concepts and methods continue to emerge, the overall cure rate of malignant tumors is still low. . American scholar Judah Folkman reported that tumor growth depends on the formation of new blood vessels. During the growth of tumor tissue, new blood vessel formation is often induced, that is, the process of forming new capillaries from existing blood vessels. Studies have shown that the diameter or thickness of the tumor tissue block reaches 1-2mm 3 At this time, if th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/42A61K47/36A61K9/14A61K9/19A61P35/00A61K31/337
Inventor 李静韩晓凤龚慕辛李潇
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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