Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes.
Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes.
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DOI：
10.1016/j.ijpharm.2011.05.082
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发表时间：
2011-09-15
影响因子：
5.8
通讯作者：
Torchilin, Vladimir P.
中科院分区：
文献类型：
--
作者：
Patel, Niravkumar R.;Rathi, Alok;Mongayt, Dmitriy;Torchilin, Vladimir P.
肿瘤多药耐药（multidrug resistance，MDR）是肿瘤化疗成功的主要障碍之一，而MDR的产生往往是由于药物外排转运泵如P-糖蛋白（P-glycoprotein，P-gp）过度表达所致。高效的第三代P-gp抑制剂，如tariquidar，在克服MDR方面显示出有希望的结果。然而，P-gp也在正常组织如血脑屏障、胃肠道、肝、脾和肾中表达。为了最大限度地发挥P-gp抑制剂的疗效并降低其全身毒性，重要的是限制P-gp抑制剂和抗癌药物在正常组织中的暴露，并增加它们与肿瘤细胞的共定位。在这项研究中，我们研究了使用长循环脂质体将P-gp抑制剂塔里克达和细胞毒性药物紫杉醇共同递送到肿瘤细胞中以逆转MDR。Tariquidar和紫杉醇负载的长循环脂质体显示出对紫杉醇的耐药变体的显著再敏感性，这可能与肿瘤细胞中紫杉醇积累增加相关。这些结果表明，P-gp抑制剂tariquidar和细胞毒性诱导剂紫杉醇的共同递送看起来像是克服MDR的有希望的方法。
One of the major obstacles to the success of cancer chemotherapy is the multidrug resistance (MDR) often resulting due to the overexpression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results in overcoming the MDR. However, P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. To maximize the efficacy of P-gp inhibitor and reduce the systemic toxicity, it is important to limit the exposure of P-gp inhibitors and the anticancer drugs to normal tissues and increase their co-localization with tumor cells. In this study, we have investigated the co-delivery of the P-gp inhibitor, tariquidar, and cytotoxic drug, paclitaxel, into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar- and paclitaxel-loaded long-circulating liposomes showed significant resensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of paclitaxel in tumor cells. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, paclitaxel, looks like a promising approach to overcome the MDR.
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