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Method for preparing coupled article of polyasparamide derivant and adriablastina, and uses thereof

A technology of polyasparagine and derivatives is applied in the field of biomedicine to achieve the effects of retaining anticancer activity, good water solubility, and reducing toxic and side effects

Active Publication Date: 2008-06-11
合肥硕健医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The conjugation of doxorubicin to PHEA, especially this galactosylated PHEA, has not been reported

Method used

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  • Method for preparing coupled article of polyasparamide derivant and adriablastina, and uses thereof
  • Method for preparing coupled article of polyasparamide derivant and adriablastina, and uses thereof
  • Method for preparing coupled article of polyasparamide derivant and adriablastina, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the preparation of polyasparagine derivative (Gal-PHEA-suc)

[0032] Weigh 2.5 g of PHEA and dissolve it in 100 ml of DMF, add 2.5 g of succinic anhydride, react at room temperature for 6 hours, then dialyze with distilled water and freeze-dry to obtain PHEA-Suc. Infrared spectrum analysis is shown in Figure 1, the product has a characteristic peak ν c＝o : 1738.5cm -1 , ν as c-o-c : 1164.7cm -1 , Elemental analysis shows that the substitution degree of succinic acid group is 43%.

[0033] Weigh 2 grams of N,N'-carbonyldiimidazole (CDI) and 1.5 grams of lactobionic acid and dissolve them in 30ml of anhydrous DMF, add the CDI solution to the lactobionic acid solution drop by drop at 0°C, and keep it for 4 hours; weigh 1 g of PHEA-suc, dissolved in 20 ml of anhydrous DMF, was added dropwise to the above solution, reacted at 0°C for 15 minutes, added a few drops of triethylamine as a catalyst, and stirred at room temperature for four days. Then it was dia...

Embodiment 2

[0034] Example 2: Preparation of polyasparagine derivative-doxorubicin conjugate (Gal-PHEA-DOX)

[0035]Weigh 0.5g EDC and dissolve in 20ml DMF, 0.125g DOX, stir to dissolve. 0.5 g Gal-PHEA-suc was dissolved in 10 ml DMF, then mixed with the above-mentioned doxorubicin solution, and stirred at room temperature for 24 hours in the dark. The reaction product was dialyzed with double distilled water for 4 days, and freeze-dried to obtain Gal-PHEA-DOX. This process was also carried out in the dark. The doxorubicin content of Gal-PHEA-DOX detected by ultraviolet and visible light was 9.7wt%.

Embodiment 3

[0036] Example 3: Inhibition of Gal-PHEA-suc and Gal-PHEA-DOX on the growth of human cervical cancer cell Hela and liver cancer cell HepG2

[0037] Press 1×10 4 Density per well Transfer the Hela and HepG2 cells in the logarithmic growth phase to 96-well plates, add 100 μl 1640 medium (10% serum + double antibody), and culture for 24 hours; take PHEA, Gal-PHEA-suc , DOX and Gal-PHEA-DOX were diluted with culture medium to a preset concentration gradient, and 100 μl was added to each well, and cultured in a 37°C incubator; the culture was terminated after the set time, and the cell viability was measured by the MTT method. Figure 2 and Figure 3 show that after 24 hours of action, PHEA and Gal-PHEA-suc have no toxicity to Hela and HepG2 when the concentration is lower than 0.75mg / ml, and the cytotoxicity is still very small when the concentration rises to 1mg / ml. Figure 4 and Figure 5 show that after being incubated with cells for 48 hours, Gal-PHEA-DOX has an inhibitory effect...

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Abstract

The invention belongs to the biomedical technical field, and in particular relates to a synthesis of targeting macromolecular drug carriers and a synthesis of macromolecular pro-drug after the pro-drug is coupled with anti-cancer drug adriamycin. The carrier relates to a derivative of alpha and beta-polymer-(2-hydroxyethyl)-L-asparagine, modifies targeting group galactosyl and active group succinyl acyl on hydroxy group, and is a safe drug carrier with hepar targeting. The macromolecular pro-drug which is coupled with anti-cancer drug adriamycin reserves the antineoplastic function of adriamycin, lowers the toxic and side effect of adriamycin to bodies, and can be developed into one adriamycin pro-drug with hepar targeting.

Description

1. Technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a preparation method of a derivative of polyasparagine, and a preparation method and application of its conjugate with anticancer drug doxorubicin. 2. Background technology [0002] In recent years, targeted drug delivery system has attracted more and more attention. It selectively distributes drugs to lesion sites, reduces the side effects of drugs on normal tissues, and improves drug utilization. Macromolecular prodrugs (macromolecular prodrugs) is a kind of targeted drug delivery system, and its design model includes a polymer carrier, a small molecule active drug connected to the carrier, and a targeting group (targeting group). The linker (spacer groups) connecting the carrier and the small molecule drug. It is characterized by controlled release and targeting. [0003] Doxorubicin (DOX, doxorubicin) is a broad-spectrum, potent anthracycline antineoplast...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/704A61K47/34A61P35/00A61K47/64
Inventor 张峻峰成晓云陈江宁夏苏华刁华佳
Owner 合肥硕健医药科技有限公司
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