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DOX-P micelle with anti-tumor drug resistance and preparation method thereof

A DOX-P, drug-resistant technology, applied in the field of DOX-P micelles and their preparation, can solve the problems of non-degradation and accumulation of polyethylene glycol, avoid protein adsorption, high encapsulation efficiency, and drug loading capacity. high effect

Inactive Publication Date: 2013-03-27
吴燕
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Some polymer-drug conjugates have entered the clinical trial stage one after another, and some polymer-drug conjugates have been approved for marketing, but they are mainly polyethylene glycol (PEG)-anti-tumor drug conjugates. Polyethylene glycol cannot be degraded in vivo, and it will accumulate after long-term application, which has potential safety problems
However, poloxamer is relatively safe, but there is no research report on the application of poloxamer and antineoplastic drug doxorubicin to form a conjugate to overcome tumor drug resistance.

Method used

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  • DOX-P micelle with anti-tumor drug resistance and preparation method thereof
  • DOX-P micelle with anti-tumor drug resistance and preparation method thereof
  • DOX-P micelle with anti-tumor drug resistance and preparation method thereof

Examples

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Embodiment 1

[0029] Synthesis of poloxamer 188-doxorubicin conjugate: take 10mmol poloxamer 188, 25mmol succinic anhydride, 20mmol DMAP, 20mmol ethylenediamine, and use 30ml dioxane as an organic solvent, and stir at room temperature for 24h. After the reaction, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 7kD, dialyzed for 48 hours using dioxane as the dialysis medium, and freeze-dried to obtain a poloxamer polymer with a carboxyl group at the end; take 10 mmol of carboxyl group at the end Poloxamer polymer, 20mmol doxorubicin, 15mmol EDC (or DCC or EDC·HCL or DIC or DPPA or p-toluenesulfonyl azide or 2,4,6-triisopropylbenzenesulfonyl azide), 15mmol NHS (or sulfo-NHS or DEPBT or HOBT), dissolved in 30ml N,N-dimethylformamide (DMF), DMF can also be replaced with dichloromethane, methyl chloride furan, dimethyl sulfoxide or di Other organic solvents such as oxyhexane, preferably DMF. Then, under the protection of light and nitrogen, stir and re...

Embodiment 2

[0030] Example 2 Synthesis of Poloxamer 188-Adriamycin Conjugate

[0031]Synthesis of poloxamer 188-doxorubicin conjugate: take 10mmol poloxamer 188, 25mmol succinic anhydride, 20mmol DMAP, 20mmol ethylenediamine, and use 30ml dioxane as an organic solvent, and stir at room temperature for 24h. After the reaction, the reaction solution was transferred to a dialysis bag with a molecular weight cut-off of 7kD, dialyzed for 48 hours using dioxane as the dialysis medium, and freeze-dried to obtain a poloxamer polymer with a carboxyl group at the end; take 10 mmol of carboxyl group at the end Poloxamer polymer, 30mmol doxorubicin, 15mmol EDC, 15mmol NHS, dissolved in 30ml N,N-dimethylformamide (DMF), protected from light, under nitrogen protection, stirred at room temperature for 24h; after the reaction Transfer the reaction solution to a dialysis bag, use 1000ml DMF as the dialysis medium, and dialyze for 24 hours, and change the dialysis medium every 6 hours during the dialysis p...

Embodiment 3

[0032] Example 3 Preparation and Characterization of Poloxamer 188-Adriamycin Conjugate Micelle

[0033] Preparation of poloxamer 188-doxorubicin conjugate micelles: 100 mg of poloxamer 188-doxorubicin conjugate obtained in Example 1 was dissolved in 10 ml of water, and high-pressure homogeneous circulation was performed twice under ice bath, 0.22 Filter with a μm filter membrane to obtain poloxamer 188-doxorubicin conjugate micelles.

[0034] Characterization observation: observe the poloxamer 188-doxorubicin conjugate micelles with transmission electron microscope (TEM, Hitachi, H-7500, Japan), record the shape and particle size of the micelles, and determine the doxorubicin by HPLC The changes in the microscopic properties and drug content over time were observed, and the changes in micelle particle size and potential were measured by a nanoparticle size and potentiodynamic analyzer (Malvern Nano ZS90).

[0035] Table 1 Characterization observation results of poloxamer 188...

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Abstract

The invention discloses poloxamer-adriamycin conjugate (DOX-P) micelle with anti-tumor drug resistance and a preparation method of the DOX-P micelle. The synthetic process of the DOX-P comprises the steps of firstly, reacting poloxamer with succinic anhydride to obtain high-molecular polymer of which the tail end contains carboxyl; and then, directly bonding the carboxyl at the tail end of the polymer with primaquine group in the adriamycin in an amido bond mode. The DOX-P has the capability of forming the micelle; and compared with the adriamycin bulk drug, the adriamycin subjected to covalent binding in the DOX-P micelle has the advantages that the anti-tumor activity of the adriamycin is maintained, the drug resistance of the tumor is overcome, and the stability of the adriamycin is better than that of poloxamer micelle.

Description

【Technical field】 [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a DOX-P micelle with antitumor drug resistance and a preparation method thereof. 【Background technique】 [0002] In tumor chemotherapy, it is found that more than 90% of chemotherapy drugs will be absorbed by normal tissues, with severe side effects, and tumor cells will develop drug resistance to most chemotherapy drugs. [0003] Doxorubicin is an anthracycline antibiotic with broad-spectrum antitumor effects and is clinically used to treat leukemia, lymphoma and solid tumors. However, its application is limited due to its strong cardiotoxicity and tumor cell resistance to it. [0004] Polymer-drug conjugates are a very effective way to increase drug water solubility and drug loading. It connects small molecule drugs to macromolecular carriers to make polymer prodrugs, especially nanoscale polymeric particles. Its small size effect and surface and interface effects h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/704A61K9/10A61P31/00A61P35/00C08G65/333
Inventor 吴燕吴诚赵应征孙昌正
Owner 吴燕
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