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ROS response type heparin polysaccharide nano prodrug compound based on click reaction, nano preparation and preparation method and application of ROS response type heparin polysaccharide nano prodrug compound

A click reaction, polysaccharide-like technology, which can be used in drug combinations, pharmaceutical formulations, active ingredients of heterocyclic compounds, etc., can solve problems such as low synthesis conversion efficiency, inability to control the synthesis ratio of different drugs, and waste of raw materials.

Active Publication Date: 2020-11-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] One of the technical problems solved by the present invention: the present invention provides a method for preparing a reactive oxygen species (reactiveoxygen species, ROS) responsive heparin-like polysaccharide nano-prodrug complex based on a click reaction, so as to solve the problem of low synthesis and conversion efficiency of nano-prodrugs at present, Waste of raw materials and technical problems of uncontrollable synthesis ratio of different drugs

Method used

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  • ROS response type heparin polysaccharide nano prodrug compound based on click reaction, nano preparation and preparation method and application of ROS response type heparin polysaccharide nano prodrug compound
  • ROS response type heparin polysaccharide nano prodrug compound based on click reaction, nano preparation and preparation method and application of ROS response type heparin polysaccharide nano prodrug compound
  • ROS response type heparin polysaccharide nano prodrug compound based on click reaction, nano preparation and preparation method and application of ROS response type heparin polysaccharide nano prodrug compound

Examples

Experimental program
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Effect test

Embodiment 1

[0062] Example 1: Preparation of ROS-responsive unfractionated heparin-lonidamine-androquinol prodrug complex based on click reaction

[0063] Weigh 2 mmol of unfractionated heparin and dissolve it in 10 mL of N,N-dimethylformamide, dissolve at 60°C, add N,N’-carbonyldiimidazole under nitrogen protection and ice bath conditions to activate the carboxyl group of unfractionated heparin. After activation in ice bath for 1 h, add 5 mL of 2-azidoethylamine solution dissolved in N,N-dimethylformamide (unfractionated heparin: N,N'-carbonyldiimidazole: 2-azidoethylamine The molar ratio is 1:8:5), and slowly added dropwise to the unfractionated heparin solution. After reacting for 48 hours, 5 times the volume of glacial ether was added to precipitate, and the precipitate was obtained by centrifugation. Lower the probe and sonicate for 20 minutes, dialyze in distilled water, and dry in vacuum to obtain azide-modified unfractionated heparin. Weigh an appropriate amount of azide-modified...

Embodiment 2

[0070] Example 2: Preparation of ROS-responsive low molecular weight heparin-aspirin-gambogic acid prodrug complex based on click reaction

[0071] Weigh 2 mmol of low molecular weight heparin and dissolve it in 10 mL of formamide, dissolve in an oil bath at 60°C, and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide activates the carboxyl group of low molecular weight heparin. After activation at 0°C for 0.5 h, add 5 mL of 2-azidoethanol solution dissolved in formamide (low molecular weight heparin: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: The molar ratio of N-hydroxysuccinimide:2-azidoethanol is 1:4:4:2), slowly added dropwise to the low molecular weight heparin solution, and after 24 hours of reaction, 5 times the volume of ice methanol was added to precipitate , the precipitate was obtained by suction filtration, redissolved with an appropriate amount of distilled water, centrifuged at 3000rpm for 10min, ultrasoni...

Embodiment 3

[0080] Example 3: Preparation of ROS-responsive desulfated heparin-DHEA-selumetinib prodrug complex based on click reaction

[0081]Weigh 2 mmol of desulfurized heparin and dissolve it in 10 mL of N,N-dimethylacetamide, dissolve in an oil bath at 60°C, add N,N'-dicyclohexyl carboximide and 4-dimethyl Aminopyridine, activates the carboxyl group of desulfated heparin. After activation in ice bath for 2 h, add 2-azido-N-(2-hydroxyethyl)ethyl dissolved in a mixed solvent of formamide and N,N-dimethylacetamide (v:v=1:1) Amide solution 5mL (desulfated heparin: N,N'-dicyclohexyl carboximide: 4-dimethylaminopyridine: 2-azido-N-(2-hydroxyethyl) acetamide molar ratio is 1:10:10:3), slowly added dropwise to the desulfated heparin solution, and reacted in the dark for 36 hours, then added 5 times the volume of ice methanol to precipitate, and the precipitate was obtained by suction filtration, redissolved with an appropriate amount of distilled water, centrifuged at 3000rpm for 10min, an...

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Abstract

The invention discloses an ROS response type heparin polysaccharide nanometer prodrug compound based on a click reaction, a nanometer preparation and a preparation method and application of the nanometer preparation. According to the nano prodrug compound, hydrophilic heparin polysaccharide is used as a matrix to be covalently coupled with two hydrophobic anti-tumor drugs in proportion through click reaction after functionalization, and is covalently combined with a targeting ligand. Compared with the prior art, the method has the advantages that excessive prodrug raw materials are prevented from being added, the proportions of different drug raw materials are controllable, and the synthesis conversion rate is high; the prodrug compound and the nano preparation have tumor specificity and targeting property, and are rapid and efficient in drug release; the prodrug compound realizes a multi-stage combination strategy of tumor treatment drugs and exerts a synergistic treatment effect of different treatment modes; the prodrug compound and the nano preparation have the advantages of strong activity, good water solubility and high stability; according to the prodrug compound and the nanopreparation, the risk of bleeding induced by heparin polysaccharide is reduced.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a novel nano-prodrug compound and nano-preparation, specifically a ROS-responsive heparin-like polysaccharide nano-prodrug compound and nano-preparation based on a click reaction, a preparation method and application thereof. Background technique [0002] Malignant tumor is one of the main killers of human beings at present. With the increase of morbidity and mortality year by year, it is urgent to find a safe and effective treatment. At present, the means of tumor treatment include surgical resection, radiotherapy and chemotherapy. However, surgical treatment has limitations and trauma; the side effects of radiotherapy will bring great pain to patients; chemotherapy is currently the most commonly used treatment for cancer, but it generally has poor selectivity and poor drug solubility. , Tumor prone to tolerance and other issues. Therefore, it will be accompanied by se...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/61A61K41/00A61K45/06A61K31/727A61K31/416A61K31/122A61K31/616A61K31/352A61K31/5685A61K31/37A61K31/4184A61K31/5415A61K31/519A61K31/475A61K31/337A61K31/196A61K31/704A61K31/56A61K31/405A61P35/00C08B37/10
CPCA61K47/61A61K41/0057A61K41/0071A61K45/06A61K31/727A61K31/416A61K31/122A61K31/616A61K31/352A61K31/5685A61K31/37A61K31/4184A61K31/5415A61K31/519A61K31/475A61K31/337A61K31/196A61K31/704A61K31/56A61K31/405A61P35/00C08B37/0075A61K2300/00
Inventor 姚静乔佳男刘姝慧
Owner CHINA PHARM UNIV
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