Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP.
Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP.
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DOI：
10.1158/0008-5472.can-08-2747
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Mumper RJ
中科院分区：
文献类型：
--
作者：
Dong X;Mattingly CA;Tseng MT;Cho MJ;Liu Y;Adams VR;Mumper RJ
为了测试纳米颗粒（NP）制剂克服P-gp介导的多药耐药性（MDR）的能力，制备了几种不同的多柔比星（Dox）和紫杉醇（PX）负载的固体脂质NP。Dox NP在Pgp过表达的人癌细胞中显示出比游离Dox低6-8倍的IC 50值。在P-gp过表达细胞中，PX NP的IC 50值比Taxol®低9倍以上。采用一系列体外细胞试验，包括定量研究摄取和流出，抑制钙黄绿素乙酰氧基甲酯（钙黄绿素AM）流出，ATP水平的改变，膜完整性，线粒体膜电位，细胞凋亡和细胞毒性。在P-gp过表达细胞中，观察到基于NP的制剂对Dox的摄取增强和保留延长。钙黄绿素AM和ATP测定证实，空白NP抑制P-gp和瞬时耗尽ATP。与所有对照组相比，静脉注射聚乙二醇化PX BTM NP在携带耐药NCI/ADR-RES肿瘤的裸鼠中显示出显著的抗癌功效。纳米粒可用于靶向药物和生物学机制，以通过P-gp抑制和ATP消耗来克服MDR。
To test the ability of nanoparticle (NP) formulations to overcome P-gp-mediated multidrug resistance (MDR), several different doxorubicin (Dox) and paclitaxel (PX)-loaded solid lipid NPs were prepared. Dox NPs showed 6-8-fold lower IC50 values in Pgp overexpressing human cancer cells than those of free Dox. The IC50 value of PX NPs was over 9-fold lower than that of Taxol® in P-gp-overexpressing cells. A series of in-vitro cell assays were used including quantitative studies on uptake and efflux, inhibition of calcein acetoxymethylester (Calcein AM) efflux, alteration of ATP levels, membrane integrity, mitochondrial membrane potential, apoptosis and cytotoxicity. Enhanced uptake and prolonged retention of Dox were observed with NP-based formulations in P-gp-overexpressing cells. Calcein AM and ATP assays confirmed that blank NPs inhibited P-gp and transiently depleted ATP. Intravenous injection of pegylated PX BTM NPs showed marked anticancer efficacy in nude mice bearing resistant NCI/ADR-RES tumors versus all control groups. NPs may be used to both target drug and biological mechanisms to overcome MDR via P-gp inhibition and ATP depletion.