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Doxorubicin bonding medicine and preparation method thereof

A doxorubicin-bonded drug technology, applied in the field of doxorubicin-bonded drug and its preparation, can solve the problems of cumbersome preparation process, too stable chemical bond, low drug loading, etc., and achieves enhanced drug effect and good biological phase. capacitive effect

Active Publication Date: 2013-02-20
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, the above two doxorubicin-bonded drugs have problems such as too stable chemical bonds, low drug loading, and lack of intelligence in the release of doxorubicin.
Biomaterials (Vol.31, p1360-1371, 2010) disclosed a carboxyl group modified by polyethylene glycol monomethyl ether and cis-3-carboxyglutaconic anhydride on the surface amino groups of polyamide-amine dendrimers Doxorubicin, resulting in a polymer doxorubicin-bonded drug, which can be released quickly in tumor tissues and cells under acidic conditions, thereby realizing the intelligence of drug release, but the doxorubicin bond The carrier material used in the drug combination is polyamide-amine dendrimers, and its preparation process is cumbersome and has poor biocompatibility, which is not conducive to the practical application of doxorubicin-bonded drugs

Method used

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  • Doxorubicin bonding medicine and preparation method thereof
  • Doxorubicin bonding medicine and preparation method thereof
  • Doxorubicin bonding medicine and preparation method thereof

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preparation example Construction

[0042] The present invention also provides a preparation method of doxorubicin-bonded drug, comprising the following steps:

[0043]Dextran, carboxylated doxorubicin derivatives, lactobionic acid with the structure of formula (V) and folic acid with the structure of formula (VI) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiazyme Amine·hydrochloride and 4-dimethylaminopyridine are reacted in an organic solvent to obtain a doxorubicin bonded drug, and the carboxylated doxorubicin derivative has formula (VII-a), formula (VII-b), Formula (VII-c) or formula (VII-d) structure:

[0044]

[0045]

[0046] In the present invention, dextran, carboxylated doxorubicin derivatives, lactobionic acid with a structure of formula (V) and folic acid with a structure of formula (VI) are first added to an organic solvent, and then 1-(3-dimethylamino Propyl)-3-ethylcarbodiimide·hydrochloride and 4-dimethylaminopyridine were reacted to obtain a doxorubicin-bonded drug. In the present inventi...

Embodiment 1

[0057] Put 580.0mg (0.001mol) of doxorubicin hydrochloride, 156.1mg (0.001mol) of cis-3-carboxyglutaconic anhydride and 101.2mg (0.001mol) of triethylamine in a dry reaction flask, and add 5mL Anhydrous N,N-dimethylformamide was dissolved, and reacted at 25°C for 24 hours under the condition of stirring with a stirrer. After the reaction was completed, pour the obtained reaction mixture into 100 mL of ethyl acetate to dilute, and dilute with saturated chloride Washing with aqueous sodium solution, drying, filtering and concentrating to obtain carboxylated doxorubicin derivatives.

[0058] Carry out nuclear magnetic resonance analysis to the doxorubicin derivative of described carboxylation, the result sees figure 1 , figure 1 The hydrogen nuclear magnetic resonance spectrum of the carboxylated doxorubicin derivatives prepared for Example 1 of the present invention; the carboxylated doxorubicin derivatives were subjected to infrared analysis, and the results can be found in ...

Embodiment 2

[0060] Put 580.0mg (0.001mol) of doxorubicin hydrochloride, 152.2mg (0.001mol) of 1,2-dicarboxycyclohexene anhydride and 101.2mg (0.001mol) of triethylamine in a dry reaction bottle, add 5mL Anhydrous N,N-dimethylformamide was dissolved, and reacted at 25°C for 24 hours under the condition of stirring with a stirrer. After the reaction was completed, pour the obtained reaction mixture into 100 mL of ethyl acetate to dilute, and dilute with saturated chloride After washing with aqueous sodium solution, drying, filtering and concentrating, carboxylated doxorubicin derivatives are obtained.

[0061] The carboxylated doxorubicin derivatives were subjected to nuclear magnetic resonance analysis and infrared analysis, and the results showed that the carboxylated doxorubicin derivatives prepared in Example 2 of the present invention had the structure of formula (II-a).

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Abstract

The invention provides a doxorubicin bonding medicine. The doxorubicin bonding medicine comprises a first repeating unit with a structure shown in a formula (I), a second repeating unit with a structure shown in a formula (II), a third repeating unit with a structure shown in a formula (III) and a fourth repeating unit with a structure shown in a formula (IV). The invention further provides a method for preparing the doxorubicin bonding medicine. According to the doxorubicin bonding medicine, glucan, carboxylation doxorubicin derivatives, lactobionic acid and folic acid are taken as raw materials to be subjected to condensation reaction, so that the doxorubicin bonding medicine is obtained, wherein the lactobionic acid and the folic acid have active targeting functions. The doxorubicin bonding medicine provided by the invention can be concentrated on tumor locations through the increased permeation and retention effects and the active targeting functions; and mover, the polymer doxorubicin bonding medicine provided by the invention has pH responsiveness, doxorubicin which is bonded on the polymer medicine through amido bonds can be quickly released in tumor tissues or tumor cells under the pH condition, and thus, the medicine effectiveness is increased.

Description

technical field [0001] The invention relates to the technical field of polymer drugs, in particular to a doxorubicin-bonded drug and a preparation method thereof. Background technique [0002] Doxorubicin, also known as daunorubicin, daunorubicin, doxorubicin or ADR, is a broad-spectrum anti-tumor drug of anthracycline antibiotics. It is a non-specific drug for the cell cycle and has the strongest effect on the S phase , It also has effects on M, G1 and G2 phases, and its mechanism of action is to embed DNA molecules, destroy nucleic acid structures and inhibit the synthesis of biological macromolecules. Doxorubicin is mainly used in the treatment of acute leukemia, malignant lymphoma, liver cancer, lung cancer, gastric cancer, esophageal cancer, cervical cancer, bladder cancer, testicular cancer, thyroid cancer, soft tissue tumors, osteosarcoma and neuroblastoma, etc. At present, the main clinical administration method of doxorubicin is intravenous infusion. However, after...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704A61P35/00
CPCA61K47/48A61K31/704A61K47/4823A61K47/48092A61K47/48107A61K47/549A61K47/551A61K47/61A61P35/00A61P35/02C07H15/04
Inventor 庄秀丽丁建勋张建成陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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