Poloxamer-doxorubicin conjugate with anti-tumor effect and preparation method thereof

An anti-tumor effect, poloxamer technology, applied in the field of poloxamer-doxorubicin conjugate and its preparation, can solve the problems of accumulation, non-degradation of polyethylene glycol, etc., achieve high encapsulation efficiency, Good stability and enhanced amphiphilic effect

Inactive Publication Date: 2015-12-02
WENZHOU MEDICAL UNIV
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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 antitumor drug doxorubicin to form a conjugate to exert antitumor effect.

Method used

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  • Poloxamer-doxorubicin conjugate with anti-tumor effect and preparation method thereof
  • Poloxamer-doxorubicin conjugate with anti-tumor effect and preparation method thereof
  • Poloxamer-doxorubicin conjugate with anti-tumor effect and preparation method thereof

Examples

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Effect test

Embodiment 1

[0029] Example 1 Synthesis of Poloxamer 188-Adriamycin Conjugate

[0030] 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, 15mmol NHS were dissolved in 30ml N,N-dimethylformamide (DMF), protected from light and nitrogen, stirred at room temperature for 24h; Transfer to a dialysis bag, use 1000ml DMF as the dialysis medium, dialyze for 24 hours, change the dialysis medium every 6 hours during the dialysis process; then use 1000ml ultrapure water as the dialysis me...

Embodiment 2

[0031] Example 2 Synthesis of Poloxamer 188-Adriamycin Conjugate

[0032]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 were dissolved in 30ml N,N-dimethylformamide (DMF), protected from light and nitrogen, stirred at room temperature for 24h; Transfer to a dialysis bag, use 1000ml DMF as the dialysis medium, dialyze for 24 hours, change the dialysis medium every 6 hours during the dialysis process; then use 1000ml ultrapure water as the dialysis med...

Embodiment 3

[0033] Example 3 Synthesis of Poloxamer 188-Adriamycin Conjugate

[0034] 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, 5mmol doxorubicin, 15mmol EDC, 15mmol NHS were dissolved in 30ml N,N-dimethylformamide (DMF), protected from light and under nitrogen, stirred at room temperature for 24h; Transfer to a dialysis bag, use 1000ml DMF as the dialysis medium, dialyze for 24 hours, change the dialysis medium every 6 hours during the dialysis process; then use 1000ml ultrapure water as the dialys...

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Abstract

The invention discloses a poloxamer-adriamycin conjugate with an anti-tumor effect and a preparation method thereof. The poloxamer-adriamycin conjugate has micelle property, is a high-molecular polymer which contains terminal carboxyl group and is prepared by reaction between poloxamer and succinic anhydride, and the terminal carboxyl group in the polymer and primary amino radical in adriamycin are directly bound in an amido link way. Compared with an adriamycin raw material drug, the poloxamer-adriamycin conjugate has the following advantages: the anti-tumor activity of the covalent bonding adriamycin in the poloxamer-adriamycin conjugate is maintained, the drug resistance of tumor is reduced; the poloxamer-adriamycin conjugate has the property of self-assembly formed micelle, and the critical micelle concentration of the conjugate is lower than that of polyxamer; and the micelle of the poloxamer-adriamycin conjugate can be entrapped with other medicaments with the anti-tumor effect in a physical entrapping mode, so that the aim of combined treatment of anti-tumor medicaments can be achieved.

Description

【Technical field】 [0001] The invention belongs to the field of pharmaceutical preparations, and relates to a poloxamer-doxorubicin conjugate with antitumor effect 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/704A61P35/00A61K47/34
Inventor 赵应征孙昌正李校堃郭平金利泰林绍强梁广高红昌林丽蔡琳张翼吕海峰万常伟
Owner WENZHOU MEDICAL UNIV
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