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Adriamycin-bonded drug and preparation method thereof

A technology of doxorubicin and bonded drugs, which is applied in the field of doxorubicin bonded drugs and its preparation, can solve the problems of over-stable chemical bonds, cumbersome preparation process, and low drug loading, and achieve good biocompatibility and enhanced The effect of drug effects

Active Publication Date: 2016-08-24
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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) discloses a carboxyl group modified by polyethylene glycol monomethyl ether and cis-3-carboxyglutaconic anhydride on the surface amino group 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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  • Adriamycin-bonded drug and preparation method thereof
  • Adriamycin-bonded drug and preparation method thereof
  • Adriamycin-bonded drug and preparation method thereof

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preparation example Construction

[0043] The present invention also provides a preparation method of doxorubicin-bonded drug, comprising the following steps:

[0044] 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-ethylcarbodiethylene Amine hydrochloride and 4-dimethylaminopyridine react 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:

[0045]

[0046]

[0047] In the present invention, first, dextran, carboxylated doxorubicin derivatives, lactobionic acid with a structure of formula (V) and folic acid with a structure of formula (VI) are 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 invention,...

Embodiment 1

[0058] 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.

[0059] 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

[0061] 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 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 After washing with aqueous sodium solution, drying, filtering and concentrating, carboxylated doxorubicin derivatives are obtained.

[0062] 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 present invention provides a doxorubicin conjugate drug, comprising a first repeating unit with a structure of formula (I), a second repeating unit of a structure of formula (II), a third repeating unit of a structure of formula (III) and a structure of formula (IV) The fourth repeating unit of the structure. The invention also provides a preparation method of the doxorubicin-bonded drug. The invention uses dextran, carboxylated doxorubicin derivatives, lactobionic acid and folic acid as raw materials to undergo condensation reaction to obtain the doxorubicin bonded drug. Among them, lactobionic acid and folic acid have an active targeting function, and the doxorubicin-bonded drug provided by the present invention can realize the aggregation of the drug at the tumor site through enhanced penetration and retention effects and active targeting function. At the same time, the polymer doxorubicin-bonded drug provided by the present invention has pH responsiveness, and the doxorubicin bound to the polymer drug through an amide bond can be released rapidly under the pH value condition in tumor tissue or tumor cells, thereby Enhance drug effect.

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