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A polyethyleneimine-polyethylene glycol-creatine copolymer micelle encapsulating doxorubicin and its preparation method

A technology of polyethyleneimine and polyethylene glycol, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as drug dependence, cardiotoxicity, and liver damage. Achieve the effects of improving stability, reducing side effects, increasing permeability and water solubility

Active Publication Date: 2015-10-28
广州智焜生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the toxicity of DOX is relatively high. In addition to bone marrow suppression and intestinal side effects, long-term use may cause irreversible cardiomyopathy due to drug dependence, causing severe cardiotoxicity and liver damage.

Method used

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  • A polyethyleneimine-polyethylene glycol-creatine copolymer micelle encapsulating doxorubicin and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0032] (1) Synthesis of dicarboxypolyethylene glycol (COOH-PEG-COOH) copolymer:

[0033] Mix 10g of polyethylene glycol-4000 and 0.75g of succinic anhydride (molar ratio is 1:3), add 0.11g of pyridine as a catalyst, pass through nitrogen protection, and react in a reflux device at 80°C for 6h to obtain light yellow COOH-PEG-COOH, spare.

[0034] (2) Amino-polyethylene glycol-carboxyl (NH 2 -PEG-COOH) copolymer synthesis:

[0035] Weigh 1g of COOH-PEG-COOH prepared in step (1) and dissolve it in 160mL of tetrahydrofuran (THF), transfer it to a two-neck flask, stir in an ice bath for 15min, then dissolve 0.04g of ethylenediamine in 30mL of THF, Then it was added dropwise into a two-neck flask, and stirred in an ice bath for 2 h. The resulting solution was dried in a vacuum oven to obtain NH 2 - Oily solid of PEG-COOH.

[0036] (3) Synthesis of creatine-polyethylene glycol-carboxylate (Cr-PEG-COOH) copolymer:

[0037] Dissolve 1.2g of creatine in 30mL of dimethyl sulfoxide (D...

Embodiment example 2

[0045] (1) Synthesis of dicarboxypolyethylene glycol (COOH-PEG-COOH) copolymer:

[0046] Mix 10g of polyethylene glycol-4000 and 1g of succinic anhydride (molar ratio is 1:4), add 0.165g of pyridine as a catalyst, pass through nitrogen protection, and react in a reflux device at 90°C for 9h to obtain light yellow COOH- PEG-COOH, spare.

[0047] (2) Amino-polyethylene glycol-carboxyl (NH 2 -PEG-COOH) copolymer synthesis:

[0048] Weigh 1g of COOH-PEG-COOH prepared in step (1) and dissolve it in 180mL of tetrahydrofuran (THF), transfer it to a two-neck flask, stir in an ice bath for 20min, then dissolve 0.045g of ethylenediamine in 40mL of THF, Then it was added dropwise into a two-neck flask, and stirred in an ice bath for 3 h. The resulting solution was dried in a vacuum oven to obtain NH 2 - Oily solid of PEG-COOH.

[0049] (3) Synthesis of creatine-polyethylene glycol-carboxylate (Cr-PEG-COOH) copolymer:

[0050] Dissolve 1.35g of creatine in 30mL of dimethyl sulfoxide...

Embodiment example 3

[0058] (1) Synthesis of dicarboxypolyethylene glycol (COOH-PEG-COOH) copolymer:

[0059] Mix 10g of polyethylene glycol-4000 and 1.25g of succinic anhydride (molar ratio is 1:5), add 0.225g of pyridine as a catalyst, pass through nitrogen protection, and react in a reflux device at 100°C for 12h to obtain light yellow COOH -PEG-COOH, spare.

[0060] (2) Amino-polyethylene glycol-carboxyl (NH 2 -PEG-COOH) copolymer synthesis:

[0061] Weigh 1g of COOH-PEG-COOH prepared in step (1) and dissolve it in 200mL of tetrahydrofuran (THF), transfer it to a two-neck flask, stir in an ice bath for 15min, then dissolve 0.05g of ethylenediamine in 50mL of THF, Then it was added dropwise into a two-necked flask, and stirred in an ice bath for 4 hours. The resulting solution was dried in a vacuum oven to obtain NH 2 - Oily solid of PEG-COOH.

[0062] (3) Synthesis of creatine-polyethylene glycol-carboxylate (Cr-PEG-COOH) copolymer:

[0063] Dissolve 1.5g of creatine in 30mL of dimethyl ...

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Abstract

The invention discloses a polyethyleneimine-polyethylene glycol-creatine copolymer micelle encapsulating doxorubicin and a preparation method thereof. The preparation method comprises: synthesizing dicarboxypolyethylene glycol copolymerization under the action of pyridine Then use ethylenediamine terminal amination to synthesize amino-polyethylene glycol-carboxyl copolymer; then creatine and amino group are connected to synthesize creatine-polyethylene glycol-carboxyl copolymer; the activated creatine-polyethylene Diol-carboxyl and polyethyleneimine react to obtain creatine-polyethylene glycol-polyethyleneimine copolymer. After dialysis, creatine-polyethylene glycol-polyethyleneimine micelles were obtained. Polyethyleneimine and creatine are connected to both ends of polyethylene glycol, and the copolymer is used as a drug carrier to form vesicles to wrap the doxorubicin. Doxorubicin is clinically used to treat malignant tumors, but it causes great damage to the normal tissues and organs of the body; in the present invention, creatine is simultaneously connected to one end of polyethylene glycol, and doxorubicin is embedded in the drug carrier, Moreover, polyethyleneimine can be connected at one end of polyethylene glycol to increase stability.

Description

technical field [0001] The invention relates to a novel anticancer drug carrier, in particular to a polyethyleneimine-polyethylene glycol-creatine copolymer micelle encapsulating doxorubicin and a preparation method thereof. Background technique [0002] The scientific name of creatine is N-methylguanidine acetic acid, which is synthesized in the body from arginine, glycine and methionine, and is a substance that stores high-energy phosphate bonds in tissues such as muscles. And creatine is an amino acid derivative that exists in the human body in nature. Since creatine is not a hormone, it will not cause interference or damage to the endocrine system of the human body, and it will not cause drug dependence or physiological side effects, so creatine has become very popular in recent years. [0003] However, since creatine has low water solubility and permeability, it is not conducive to direct consumption, so it is modified to convert it into a substance that is more conduc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/107A61K31/704A61K47/34A61P35/00
Inventor 魏坤魏诗琪邹芬
Owner 广州智焜生物科技有限公司