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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。
OBJECTIVE: Doxorubicin (DOX) is a commonly used anti-tumor drug, but its toxicity and side effects are great, and tumor cells are easily drug-resistant to DOX, which limits its clinical application. In this study, mitochondrial transmembrane potential of tumor cells with higher characteristics, the lipophilic cationic (3-propargyl) triphenylphosphonium bromide (TPP) and DOX were linked to prepare a mitochondrial targeting function of TPP-DOX, in order to achieve Reverse the purpose of tumor cell resistance. Methods: DOX and TPP were used as raw materials to synthesize TPP-DOX and identified by NMR and MS. The anti-tumor activity of TPP-DOX against KB cells, A549 cells and DOX-resistant MDA-MB-231 / ADR cells was studied by MTT assay. Laser confocal microscopy was used to observe the distribution of TPP-DOX in tumor cells. Results: The toxicity of TPP-DOX to KB cells and A549 cells was lower than that of DOX. The toxicity of TPP-DOX to DOX-bearing MDA-MB-231 / ADR cells was significantly higher than DOX. Confocal laser scanning showed TPP-DOX was distributed in nucleus and mitochondria. Conclusion: TPP-DOX has the mitochondrial targeting properties, which can effectively reverse the drug resistance of tumors, and has the value of further research.