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Camptothecin prodrug gel, and preparation method and use thereof

A technology of camptothecin and prodrug, applied in the field of medicine, can solve the problems of limited application, low therapeutic effect, poor water solubility, etc., and achieves the effects of good glutathione response performance, broad clinical application prospect, and good pH response performance

Active Publication Date: 2019-04-12
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nanoscale CPT can passively target tumor tissue through the highly permeable long retention (EPR) effect, but due to the instability of simple physical encapsulation, CPT is easily leaked from the carrier circulating in vivo, resulting in severe side effects and low therapeutic efficacy
In addition, due to the very poor water solubility, the encapsulation efficiency of CPT in nanoformulations is very low, which also severely limits its application.

Method used

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  • Camptothecin prodrug gel, and preparation method and use thereof
  • Camptothecin prodrug gel, and preparation method and use thereof
  • Camptothecin prodrug gel, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of 2-((2-hydroxyethyl) disulfanyl) ethyl methacrylate (HSEMA)

[0060]

[0061] 2,2'-Dithiodiethanol (1.54g, 10mmol) and triethylamine (1.52g, 15mmol) were dissolved in 50ml of anhydrous tetrahydrofuran, and cooled to 0°C in an ice-water bath. Dissolve methacryloyl chloride (1.05, 10 mmol) in 25 mL of anhydrous tetrahydrofuran, and slowly add it dropwise to the above reaction solution under vigorous stirring. After reacting overnight at room temperature, insoluble salts were removed by filtration; then, all solvents were removed by rotary evaporation. The obtained crude product was diluted with 50 mL of ethyl acetate, and washed three times with water and saturated sodium chloride solution to remove impurities in unreacted raw materials. The organic phase was collected by separation and dried over anhydrous magnesium sulfate. The solution was concentrated by rotary evaporation, and then separated and purified by silica column, the mobile phase...

Embodiment 2

[0062] The preparation of embodiment 2CPT-ss-M

[0063]

[0064] Under a nitrogen atmosphere, camptothecin (0.70 g, 2 mmol) and triphosgene (0.2 g, 0.66 mmol) were blended in 50 mL of dry dichloromethane, followed by the addition of 4-dimethylaminopyridine (0.73 g, 6 mmol) , and stirred for 1 hour. Then HSEMA (0.55 g, 2.5 mmol) was dissolved in 10 ml of anhydrous THF, and added dropwise to the above reaction solution. After 24 hours of reaction at room temperature, the reaction mixture was filtered to remove insoluble salts; all solvent was removed by rotary evaporation. The residue was redissolved in dichloromethane, and washed twice with dilute hydrochloric acid (100 mmol / L), water, and saturated sodium chloride solution respectively. The organic layer was collected and dried over anhydrous magnesium sulfate. Concentrate the supernatant, use dichloromethane / methanol (200 / 1, v / v) as eluent, separate and purify by silica gel column, obtain light yellow camptothecin monom...

Embodiment 3

[0065] Example 3 Preparation of 2-(2-hydroxyethyl) ethyl methacrylate (HDOMA)

[0066]

[0067] 1,6-Hexanediol (1.18g, 10mmol) and triethylamine (1.52g, 15mmol) were dissolved in 50ml of anhydrous tetrahydrofuran, and cooled to 0°C in an ice-water bath. Dissolve methacryloyl chloride (1.05, 10 mmol) in 25 mL of anhydrous tetrahydrofuran, and slowly add it dropwise to the above reaction solution under vigorous stirring. After reacting overnight at room temperature, insoluble salts were removed by filtration; then, all solvents were removed by rotary evaporation. The obtained crude product was diluted with 50 mL of ethyl acetate, and washed three times with water and saturated sodium chloride solution to remove impurities in unreacted raw materials. The organic phase was collected by separation and dried over anhydrous magnesium sulfate. The solution was concentrated by rotary evaporation, then separated and purified by silica column, and the mobile phase was ethyl acetate / ...

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Abstract

The invention relates to a camptothecin prodrug gel, and a preparation method and use thereof, and belongs to the field of medicines. The present invention provides the camptothecin prodrug gel whichis prepared by polymerization of raw materials containing a camptothecin prodrug, methacrylic acid, a crosslinking agent and an initiator, wherein the structure of the camptothecin prodrug is as shownin a formula I. The PMAA-based pH / redox dual-responsive camptothecin prodrug gel provided by the invention has a particle size of a nanometer level, good pH response performance and glutathione response performance, and can rapidly release an active ingredient camptothecin in tumor cells to achieve the effect of targeted killing of the tumor cells. Biological experiments prove that the camptothecin prodrug gel of the invention can be successfully ingested by tumor cells, has significant inhibitory effect on tumor cells, exhibits obvious anti-tumor activity in vivo, and has a broad clinical application prospect.

Description

technical field [0001] The invention relates to a camptothecin prodrug gel, a preparation method and application thereof, and belongs to the field of medicine. Background technique [0002] As one of the major malignant diseases in the world, cancer seriously threatens human health and leads to a substantial increase in the global medical burden year by year. Chemotherapy is one of the most commonly used and effective treatment methods, but an ideal chemotherapy drug with good therapeutic effect on tumor tissue and low toxicity to normal tissue has not been developed yet. Camptothecin (CPT) is a pentacyclic quinoline alkaloid drug with superior antitumor effects, and has shown excellent therapeutic effects in colon cancer, lung cancer, breast cancer, ovarian cancer, melanoma and other cancers. CPT mainly inhibits the activity of the nuclear enzyme topoisomerase I (necessary for DNA replication and transcription processes), thereby breaking the connection of DNA strands and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/06A61K47/58A61K31/4745A61P35/00
CPCA61K47/58A61P35/00A61K9/06A61K31/4745
Inventor 钱志勇楚冰洋魏霞蔚
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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