Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response
Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response
复制标题
通过负载紫杉醇的具有线粒体靶向和 pH 响应的双功能脂质体克服耐药肺癌。
DOI：
10.1016/j.biomaterials.2015.02.004
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发表时间：
2015-06-01
期刊：
影响因子：
14
通讯作者：
Gu, Zhongwei
中科院分区：
文献类型：
--
作者：
Jiang, Lei;Li, Li;Gu, Zhongwei
智能脂质体的线粒体定向运输已成为一种很有前途的将抗癌药物直接输送到肿瘤部位的策略，它在杀死癌细胞，特别是具有多药耐药（MDR）的癌细胞方面具有巨大的潜力。在此，我们报道了一种新型的双功能脂质体系统，它具有细胞外pH响应和线粒体靶向特性，可以增强线粒体中的药物积累并触发耐药癌细胞的凋亡。简单地说，用2,3 -二甲基马来酸酐（DMA）修饰肽D[KLAKLAK](2) (KLA)，并与1,2 -二硬脂酰-sn-甘油-3-磷酸乙醇胺（DSPE）结合，得到DSPE- icla -DMA （DKD）脂质。然后将这种双功能DKD与其他市售脂质混合制成脂质体。在体外对人肺癌A549细胞和耐药肺癌A549/Taxol细胞的抗癌效果进行了评价。在肿瘤细胞外pH值（类似于6.8）时，脂质体可以逆转其表面电荷（负向正），促进脂质体内化。在细胞摄取后，KLA肽定向递送使这些脂质体选择性积累到线粒体中，并有利于其货物紫杉醇（PTX）释放到所需部位。具体来说，MDR癌细胞通过线粒体信号通路增强了凋亡，细胞色素c的释放和caspase-9和-3活性的增加证明了这一点。双功能脂质体对A549细胞和A549/Taxol细胞的体外治疗效果最好，对裸鼠移植的耐药肺癌A549/Taxol细胞的肿瘤生长抑制率为86.7%。总之，双功能脂质体提供了一种新的和通用的方法来克服耐多药癌症治疗。(C) 2015 Elsevier Ltd.版权所有。
Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK](2) (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-ICLA-DMA (DKD) lipid. This dual-functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (similar to 6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual-functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment. (C) 2015 Elsevier Ltd. All rights reserved.