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Carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug and preparation method and application thereof

A technology of methyl aminolevulinate and polycaprolactone, which can be used in pharmaceutical formulations, antineoplastic drugs, drug combinations, etc., can solve the problems of poor fat solubility and instability, and achieve high conversion rate and good photodynamic efficacy , good lethal effect

Pending Publication Date: 2020-05-12
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to overcome the defects of poor fat solubility and instability of MLA, the object of the present invention is to provide a carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug, which can be used as a carboxylated polycaprolactone-based photodynamic therapy The prodrug increases the amount of MLA converted into PpIX, improves the lethality of tumor cells, and then improves the effect of photodynamic therapy

Method used

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  • Carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug and preparation method and application thereof
  • Carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug and preparation method and application thereof
  • Carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Synthesis of mPEG-b-P(CL-co-BCL) and mPEG-b-P(CL-co-CCL)

[0036]

[0037] x=30, y=20.

[0038] Under argon protection, 1 g of polyethylene glycol monomethyl ether (mPEG 2k ), 2.79g 6(2)-p-methylbenzyl acetate-ε-caprolactone (6(2)-p-(CH 3 ) BCL) and 1.71g ε-caprolactone (ε-CL) were added to the dry polymerization bottle, and the polymerization bottle was placed in an oil bath at a temperature of 60°C, continuously stirred and vacuumed for 2 hours, and then 50 microliters of iso Stannous octoate (Sn(Oct) 2 ) (10mg, 0.025mmol) of the toluene solution was added to the polymerization bottle, through repeated vacuuming-argon gas operation, to remove a small amount of toluene solvent, then filled with argon in the polymerization bottle, sealed and placed in the oil at a temperature of 130 ° C The reaction was continued in the bath for 24 hours. After the reaction was completed, it was dissolved with a small amount of DCM, and then a large amount of ice anhydrous ether w...

Embodiment 2

[0047] Synthesis of mPEG-b-P(CL-co-BCL) and mPEG-b-P(CL-co-CCL)

[0048]

[0049] x=40, y=10.

[0050] Under argon protection, 1 g of polyethylene glycol monomethyl ether (mPEG 2k ), 1.395g 6(2)-p-methylbenzyl acetate-ε-caprolactone (6(2)-p-(CH 3 ) BCL) and 2.28g ε-caprolactone (ε-CL) were added to the dry polymerization bottle, and the polymerization bottle was placed in an oil bath at a temperature of 60°C, kept stirring and vacuuming for 2 hours, and then 50 microliters of iso Stannous octoate (Sn(Oct) 2 ) (10mg, 0.025mmol) of the toluene solution was added to the polymerization bottle, through repeated vacuuming-argon gas operation, to remove a small amount of toluene solvent, then filled with argon in the polymerization bottle, sealed and placed in the oil at a temperature of 130 ° C The reaction was continued in the bath for 24 hours. After the reaction was completed, it was dissolved with a small amount of DCM, and then a large amount of ice anhydrous ether was ad...

Embodiment 3

[0059] Synthesis of mPEG-b-P(CL-co-BCL) and mPEG-b-P(CL-co-CCL)

[0060]

[0061] x=20, y=30.

[0062] Under argon protection, 0.5 g polyethylene glycol monomethyl ether (mPEG 2k ), 2.093g 6(2)-p-methylbenzyl acetate-ε-caprolactone (6(2)-p-(CH 3 ) BCL) and 0.57g ε-caprolactone (ε-CL) were added to the dry polymerization bottle, and the polymerization bottle was placed in an oil bath at a temperature of 60°C, and kept stirring and vacuuming for 2 hours, and then 25 microliters of iso Stannous octoate (Sn(Oct) 2 ) (5mg, 0.0125mmol) of toluene solution was added to the polymerization bottle, through repeated vacuuming-argon gas operation, to remove a small amount of toluene solvent, then filled with argon in the polymerization bottle, sealed and placed in the oil at a temperature of 130 ° C The reaction was continued in the bath for 24 hours. After the reaction was completed, it was dissolved with a small amount of DCM, and then a large amount of ice anhydrous ether was add...

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Abstract

The invention discloses a carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug. The prodrug has a structure as shown in the specification. In the formula, x is in a range of10-40, and y is in a range of 10-40. The carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug is made into micelles. Cell experiments prove that compared with pure 5-aminolevulinic acid methyl ester, the prodrug micelles have the advantages that the amount of protoporphyrin PPIX converted from the prodrug micelles is higher, more singlet oxygen ROS is generated, and the killing performance on tumor cells is better. The 5-aminolevulinic acid methyl ester is grafted into functionalized polycaprolactone by adopting a chemical grafting method, so the fat solubility and the stability of the 5-aminolevulinic acid methyl ester are improved, a higher conversion rate is obtained, and a better photodynamic curative effect is achieved.

Description

technical field [0001] The invention belongs to the technical field of carboxylated polycaprolactone-based photodynamic therapy prodrugs, in particular to a carboxylated polycaprolactone-based 5-aminolevulinic acid methyl ester prodrug, its preparation method and application. Background technique [0002] Photodynamic therapy (PDT) is a new technology that utilizes photodynamic effect for disease diagnosis and treatment. 5-aminolevulinic acid (ALA) is a second-generation porphyrin photosensitizer developed in recent years, and 5-aminolevulinic acid methyl ester (MLA) is a Esters derivatives. ALA and MLA can be absorbed in cells and converted into protoporphyrin IX (PpIX) with strong photosensitivity. After PpIX is activated by light of a specific wavelength, it undergoes a photodynamic reaction to generate singlet oxygen with a killing effect on cells, thereby Kill tumor cells. MLA is slightly more hydrophilic than ALA, but its fat solubility is still poor, and it is unst...

Claims

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Application Information

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IPC IPC(8): C08G63/91C08G63/08C08G63/664A61K31/785A61P35/00
CPCC08G63/912C08G63/08C08G63/664A61K31/785A61P35/00
Inventor 郎美东王申春王秀丽申抒展
Owner EAST CHINA UNIV OF SCI & TECH
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