线粒体靶向TPP-DOX连接物的制备及其逆转肿瘤耐药活性研究

目的:阿霉素(DOX)是常用的抗肿瘤药物,但是它的毒副作用大,而且肿瘤细胞易对DOX产生耐药,限制了其临床应用。本研究利用肿瘤细胞线粒体跨膜电位较高的特性,将亲脂性阳离子(3-丙羧基)三苯基溴化膦(TPP)与DOX相连接制备具有线粒体靶向功能的TPP-DOX,以期达到逆转肿瘤细胞耐药的目的。方法:以DOX、TPP为原料,合成TPP-DOX,通过核磁、质谱等方法进行结构鉴定。采用MTT方法研究TPP-DOX对KB细胞、A549细胞及耐DOX肿瘤细胞MDA-MB-231/ADR的体外抗肿瘤活性。采用激光共聚焦显微镜观察TPP-DOX在肿瘤细胞内的分布。结果:TPP-DOX对KB细胞和A549细胞的毒性低于DOX,TPP-DOX对耐DOX肿瘤细胞MDA-MB-231/ADR的毒性明显大于DOX。激光共聚焦显示TPP-DOX分布于细胞核和线粒体中。结论:TPP-DOX具有线粒体靶向特性,可有效逆转肿瘤耐药,有进一步研究的价值。

Preparation of Mitochondrial Targeting TPP-DOX Conjugate to Overcoming the Drug Resistance of Doxorubicin

Objective:Doxorubicin (DOX) is a commonly used chemotherapy drug for tumor treatment. However, the severe side effects and multiple drug resistance (MDR) hinder its clinical application. The mitochondrial trans-membrane potential is relative high, thus lipophilic cations show high affinity with mitochondria. In this paper, (3-carboxyl) phenyl bromide phosphine (TPP) was conjugated with DOX to prepare mitochondria targeting TPP-DOX to overcome drug resistance of tumor cells.Methods:TPP-DOX was synthesized by connecting TPP and DOX. The structure of TPP-DOX was confirmed by 1HNMR and MS. The antitumor activity of TPP-DOX was tested in vitro against KB cells, A549 cells and MDA-MB-231/ADR cells by MTT method. The laser confocal microscope was used to observe the cellular uptake and distribution of the TPP-DOX in tumor cells.Results:TPP-DOX exhibited lower cytotoxicity than free DOX on KB cells and A549 cells, but it showed higher cytotoxicity than free DOX on MDA-MB-231/ADR cells. Confocal microscopy confirmed that TPP-DOX distributed in the mitochondria and nucleus.Conclusion:TPP-DOX can overcome drug resistance in tumor cells, and it is worthy of further investigation.