阿霉素前药的制备及体外抗肿瘤研究

The Preparation of Doxorubicin-based Prodrug and Its Anticancer Ability

目的:构建一种具有临床应用潜力的阿霉素前药胶束纳米药物。方法:采用药物阿霉素和醛基聚乙二醇单甲醚为原料,通过阿霉素的氨基和醛基聚乙二醇单甲醚中的醛基反应形成酸敏感性的亚胺键,合成制备阿霉素前药胶束。纳米粒度仪测定胶束粒子的大小和稳定性,透射电子显微镜测试粒子的形貌。细胞毒性实验评价阿霉素前药胶束的体外抗肿瘤药效。细胞吞噬实验证明阿霉素前药胶束在Hela细胞中的分布。结果:组装的阿霉素前药胶束粒子大小为155 nm,且粒子在磷酸盐缓冲液(PBS)中3天内无明显变化;当阿霉素前药胶束的药物浓度为10μg·mL^(-1)时,Hela细胞在24 h的细胞存活率为38%;阿霉素前药胶束在4 h内可被细胞吞噬且分布在细胞核周边。结论:阿霉素前药胶束能被细胞吞噬并分布到细胞核并有效介导肿瘤细胞的凋亡,是一种简单、有效的纳米制剂。

Objective:To fabricate a nanomedicine of Doxorubicin-based prodrug micelle with clinical application potential.Methods:The NH_(2) group in Doxorubicin(Dox)reacted with the CHO group in methoxy-poly(ethylene glycol)aldehyde(mPEG-CHO)to form an imine bond and construct the Dox-based prodrug micelle.The size and stability of the prodrug micelle were evaluated by dynamic light scatter(DLS)and the morphology of the micelle was observed by transmission electron microscopy(TEM).The drug efficacy and the distribution of prodrug micelle were evaluated by cell viability and cell uptake experiments respectively.Results:The assembled Dox-based prodrug micelle was 155 nm and very stable during 3 days.The Hela cell viability was 38%at 24 h treated with Dox-based prodrug micelle of 10μg·mL^(-1),Dox and the cell uptake experiment showed that the Dox-based prodrug micelle was swallowed by Hela cells and distributed to the surrounding of cell nuclei.Conclusion:The simple and effective nanomedicine of Dox-based prodrug micelle can be swallowed by Hela cells and distributed to the cell nuclei for inducing the apoptosis of Hela cells.