c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles as well as preparation and application thereof

A technology of drug-loaded micelles and chitosan, which can be used in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as serious toxic side effects, drug resistance, and unsatisfactory patient prognosis, and can inhibit the formation of new blood vessels and improve the The concentration of photosensitizer, the effect of high-efficiency photothermal conversion

Active Publication Date: 2019-06-07
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some progress has been made in surgical treatment, radiotherapy and chemotherapy, the side effects are serious, and the prognosis of patients is still unsatisfactory. The median survival period of most patients is less than 14 months, so it is urgent to find new and effective treatment
However, the effects of antibodies and small molecule inhibitors are mild and short-lived, and long-term drug resistance is likely to occur, making it difficult to achieve the ideal inhibitory effect on neovascularization

Method used

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  • c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles as well as preparation and application thereof
  • c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles as well as preparation and application thereof
  • c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1) Preparation of low molecular weight chitosan

[0038] Take 20 g of chitosan with a molecular weight of 450 kDa and a degree of deacetylation of 95%, disperse it in 1000 mL of hydrochloric acid solution with a volume ratio of 0.9%, stir in a water bath at 60°C for 12 hours, and fully swell. Slowly drop chitosanase with a weight ratio of 2% therein, and enzymolysis reaction occurs at a temperature of 60°C. Gel permeation chromatography was used to control the molecular weight of chitosan during the degradation process. After the degradation is complete, add activated carbon with a weight / volume ratio of 5% at 80°C, stir for 30 minutes, cool to room temperature, and gradually remove activated carbon with ordinary filter paper, 0.45 μm and 0.22 μm microporous membranes, and vacuum freeze-dry Low-molecular-weight chitosan is obtained, and the weight-average molecular weight of the obtained chitosan is 5-20 kDa.

[0039] (2) Synthesis of chitosan stearic acid graft

[...

Embodiment 2

[0045] (1) Preparation of low molecular weight chitosan

[0046] Take 20 g of chitosan with a molecular weight of 450 kDa and a degree of deacetylation of 95%, disperse it in 1000 mL of hydrochloric acid solution with a volume ratio of 0.9%, stir in a water bath at 60°C for 12 hours, and fully swell. Slowly drop chitosanase with a weight ratio of 2% therein, and enzymolysis reaction occurs at a temperature of 60°C. Gel permeation chromatography was used to control the molecular weight of chitosan during the degradation process. After the degradation is complete, add activated carbon with a weight / volume ratio of 5% at 80°C, stir for 30 minutes, cool to room temperature, and gradually remove activated carbon with ordinary filter paper, 0.45 μm and 0.22 μm microporous membranes, and vacuum freeze-dry Low-molecular-weight chitosan is obtained, and the weight-average molecular weight of the obtained chitosan is 5-20 kDa.

[0047] (2) Synthesis of chitosan stearic acid graft

[...

Embodiment 3

[0053] (1) Preparation of low molecular weight chitosan

[0054] Take 20 g of chitosan with a molecular weight of 450 kDa and a degree of deacetylation of 95%, disperse it in 1000 mL of hydrochloric acid solution with a volume ratio of 0.9%, stir in a water bath at 60°C for 12 hours, and fully swell. Slowly drop chitosanase with a weight ratio of 2% therein, and enzymolysis reaction occurs at a temperature of 60°C. Gel permeation chromatography was used to control the molecular weight of chitosan during the degradation process. After the degradation is complete, add activated carbon with a weight / volume ratio of 5% at 80°C, stir for 30 minutes, cool to room temperature, and gradually remove activated carbon with ordinary filter paper, 0.45 μm and 0.22 μm microporous membranes, and vacuum freeze-dry Low-molecular-weight chitosan is obtained, and the weight-average molecular weight of the obtained chitosan is 5-20 kDa.

[0055] (2) Synthesis of chitosan stearic acid graft

[...

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Abstract

The invention provides c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles. The micelles are obtained by the steps of grafting c(RGDfk) cyclic peptide to chitosan stearic acid toobtain a c(RGDfk) cyclic peptide-chitosan stearic acid graft, performing complexation on tetrabutylammonium iodide and photosensitizer indocyanine green through charge interaction to obtain photosensitizer hydrophobized indocyanine green, and performing encapsulation on the hydrophobized indocyanine green through a dialysis method to obtain the c(RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles. The drug-loaded micelles provided by the invention have dual targeting functions of brain glioma cells and neovascular endothelial cells, and can selectively deliver the photosensitizer, improve a concentration of the photosensitizer of the brain glioma cells and the tumor neovascular endothelial cells and increase stability of the photosensitizer; and after near-infrared laser illumination, indocyanine green high-efficiency photothermal conversion and reactive oxygen generation are realized, apoptosis of the brain glioma cells is induced, tumor neovascularization is inhibited, and efficacy of phototherapy against brain glioma is improved.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to the construction of a drug delivery system targeting brain glioma cells and tumor neovascular endothelial cells, in particular to a c Construction of (RGDfk) cyclic peptide-chitosan stearic acid graft drug-loaded micelles and its application in drug-loaded glioma phototherapy. Background technique [0002] Glioma is the most common intracranial malignant tumor in adults, which is highly lethal and prone to recurrence and regeneration. Although some progress has been made in surgical treatment, radiotherapy and chemotherapy, the side effects are severe, and the prognosis of patients is still unsatisfactory. [0003] Phototherapy is a new type of non-invasive local treatment method, which has remarkable curative effect and less toxic side effects. However, its oxygen-dependent properties can exacerbate the degree of hypoxia deep in the tumor. Hypoxic tumor cells trigger angiogenesis and pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00A61K9/107A61K47/36A61K41/00A61P35/00
Inventor 胡富强戴素桓孟廷廷袁弘
Owner ZHEJIANG UNIV
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