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Acid-sensitive paclitaxel prodrug and preparing method thereof and prodrug nano-micelle

A nano-micelle and paclitaxel technology, which is applied in the field of prodrug nano-micelle and acid-sensitive paclitaxel prodrug, can solve the problems of high toxicity and side effects, low bioavailability, strong hydrophobicity of paclitaxel, etc., and achieve good biocompatibility Sexuality, improvement of effect, strong effect of killing tumor cells

Active Publication Date: 2017-11-17
海南药物研究所有限责任公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the problems of paclitaxel's strong hydrophobicity, low bioavailability, and high toxicity to the human body, people have studied a variety of polymer prodrugs or drug carriers to change the way it enters the body and its distribution in the body.

Method used

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  • Acid-sensitive paclitaxel prodrug and preparing method thereof and prodrug nano-micelle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] 1) Polymerization reaction:

[0059] Add 1.29g of functionalized caprolactone monomer, 0.5g of polyethylene glycol monomethyl ether 2000 and 0.0506g of stannous octoate into a 10mL polymerization reactor. The reaction was terminated by formic acid to obtain a diblock copolymer mixture. After dissolving the reaction mixture with 5 mL of dichloromethane, the mixed solution was poured into 50 mL of methanol in an ice-water bath. The dissolution-precipitation process was repeated three times, and the filter residue was collected and vacuum-dried in a vacuum oven at 40° C. to obtain a diblock copolymer (III).

[0060] 2) Hydrolysis of ester bond

[0061] Under nitrogen protection, 1.79 g of diblock copolymer (III) was dissolved in 100 mL of dichloromethane. At 0°C, under stirring, 7.75 mL of trichloroacetic acid was slowly added dropwise to the solution. After the addition was complete, stirring was continued at 0°C for 4 hours. The solvent was evaporated under reduced ...

Embodiment 2

[0068] 1) Polymerization reaction:

[0069] Add 1.032g of functionalized caprolactone monomer, 0.4g of polyethylene glycol monomethyl ether 5000 and 0.0162g of stannous octoate into a 10mL polymerization reactor. The reaction was terminated by formic acid to obtain a diblock copolymer mixture. After dissolving the reaction mixture with 5 mL of dichloromethane, the mixed solution was poured into 50 mL of methanol in an ice-water bath. The dissolution-precipitation process was repeated three times, and the filter residue was collected and vacuum-dried in a vacuum oven at 40° C. to obtain a diblock copolymer (III).

[0070] 2) Hydrolysis of ester bond

[0071] Under nitrogen protection, 1.432 g of diblock copolymer (III) was dissolved in 100 mL of dichloromethane. 7.75 mL of trifluoroacetic acid was slowly added dropwise to the solution under stirring condition at 0°C. After the addition was complete, stirring was continued at 0°C for 4 hours. The solvent was evaporated unde...

Embodiment 3

[0077] 1) Polymerization reaction:

[0078] Add 1.032g of functionalized caprolactone monomer, 0.5g of polyethylene glycol monomethyl ether 10000 and 0.0101g of stannous octoate into a 10mL polymerization reactor. The reaction was terminated by formic acid to obtain a diblock copolymer mixture. After dissolving the reaction mixture with 5 mL of dichloromethane, the mixed solution was poured into 50 mL of methanol in an ice-water bath. The dissolution-precipitation process was repeated three times, and the filter residue was collected and vacuum-dried in a vacuum oven at 40° C. to obtain a diblock copolymer (III).

[0079] 2) Hydrolysis of ester bond

[0080] Under nitrogen protection, 1.532 g of diblock copolymer (III) was dissolved in 100 mL of dichloromethane. 7.75 mL of p-toluenesulfonic acid was slowly added dropwise to the solution under stirring condition at 0°C. After the addition was complete, stirring was continued at 0°C for 4 hours. The solvent was evaporated u...

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Abstract

The invention discloses an acid-sensitive paclitaxel prodrug and a preparing method and an application thereof. The acid-sensitive paclitaxel prodrug has a structure which is shown in the first formula. According to the acid-sensitive paclitaxel prodrug, a polymer precursor is amphipathy two-inlayed-section copolymer of vinyl ether functionlization, and drug molecules are covalently linked to the amphipathy two-inlayed-section copolymer through acetal bonds. The paclitaxel prodrug can be subjected to self-assembly in an aqueous solution, so that prodrug nano-micelle is formed, wherein a polyethylene glycol hydrophilic segment is used as the outer surface, a lateral group is used for polycaprolactone functionlization, and antineoplastic drug paclitaxel which is linked to polymer main chains through the acetal bonds is used as a hydrophobic core. The drug loading capacity of the micelle is higher, and leakage and burst release of the drug can be avoided in the body circulation process. The polymer prodrug has the pH-sensitive acetal bonds, the drug cannot be released under the weak alkaline environment in normal cells, the drug is slowly released under the acid environment in tumour cells, the tumour cells can be killed in a specificity mode, and accordingly the toxic and side effects of the drug are lowered.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to an acid-sensitive paclitaxel prodrug, a preparation method thereof and prodrug nano micelles. Background technique [0002] More than 8 million people die from cancer every year in the world, and this number is still increasing year by year. The treatment of cancer has become one of the greatest challenges and problems faced by mankind in the 21st century. With the continuous exploration of oncology, genomics, proteomics, pharmacy and other related scientific fields, many effective anti-tumor drugs have been designed and developed. However, most of the current anti-tumor drugs are small molecules, which have the disadvantages of large toxic and side effects, strong hydrophobicity, and poor bioavailability, which greatly limit the clinical application of small-molecule anti-tumor drugs. [0003] Paclitaxel is a natural product isolated from the bark of the Pacific ye...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G63/91C08G63/664A61K47/69A61K47/59A61K31/337A61K9/107A61P35/00
CPCA61K31/337C08G63/664C08G63/912
Inventor 周星孙伟翟英雷
Owner 海南药物研究所有限责任公司
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