Development of targeting lonidamine liposomes that circumvent drug-resistant cancer by acting on mitochondrial signaling pathways
Development of targeting lonidamine liposomes that circumvent drug-resistant cancer by acting on mitochondrial signaling pathways
复制标题
开发靶向氯尼达明脂质体，通过作用于线粒体信号通路来规避耐药癌症
DOI：
10.1016/j.biomaterials.2013.01.055
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发表时间：
2013-04-01
期刊：
影响因子：
14
通讯作者：
Lu, Wan-Liang
中科院分区：
文献类型：
--
作者：
Li, Nan;Zhang, Cheng-Xiang;Lu, Wan-Liang
即使面临淘汰，功能材料也可能为昂贵的药物提供新的替代品。一旦用于治疗良性前列腺肥大，美国食品和药物管理局（FDA）暂停使用氯尼达明，由于其不良的药物特性引起的肝脏问题的发生。本研究的目的是开发靶向氯尼达明脂质体与靶向表阿霉素脂质体的组合，以规避耐药癌症。对A549和耐药A549 cDDP肺癌细胞以及耐药A549 cDDP异种移植BALB/c裸鼠进行评价。将DQA-PEG（2000）-DSPE缀合物掺入脂质体中作为靶向分子。所构建的靶向氯尼达明脂质体和靶向表阿霉素脂质体的测量值约为80 nm。靶向氯尼达明脂质体可显著增强靶向表阿霉素脂质体对耐药A549 cDDP细胞的抑制作用，且呈剂量依赖性。机制研究表明，靶向脂质体选择性地积聚在线粒体中，耗散线粒体膜电位，打开线粒体通透性转换孔，并通过移位释放细胞色素C。这引发了半胱天冬酶9和3的级联反应，并激活促凋亡Bax蛋白，同时抑制抗凋亡Mcl-1蛋白，从而通过作用于线粒体信号传导途径增强细胞毒性作用。与以可比剂量施用对照相比，施用靶向氯尼达明脂质体加靶向表阿霉素脂质体后治疗耐药性A549 cDDP异种移植肿瘤模型的功效是最显著的。总之，靶向氯尼达明脂质体可用作与抗癌剂的有效联合治疗，以通过作用于线粒体信号传导通路来增强治疗耐药癌症的功效。(C)2013爱思唯尔有限公司保留所有权利。
Even when faced with elimination, functional materials may offer new alternatives to expensive drugs. Once used to treat benign prostate hypertrophy, the US Food and Drug Administration (FDA) suspended the use of lonidamine due to the occurrence of liver problems arising from its poor pharmaceutical properties. The objectives of the present study were to develop targeting lonidamine liposomes in combination with targeting epirubicin liposomes to circumvent drug-resistant cancer. Evaluations were performed on A549 and drug-resistant A549cDDP lung cancer cells and drug-resistant A549cDDP xenografted BALB/c nude mice. A DQA-PEG(2000)-DSPE conjugate was incorporated onto the liposomes as a targeting molecule. The constructed targeting lonidamine liposomes and targeting epirubicin liposomes measured were approximately 80 nm. The targeting lonidamine liposomes significantly enhanced the inhibitory effect of the targeting epirubicin liposomes in the drug-resistant A549cDDP cells in a lonidamine dose-dependent manner. Mechanism studies revealed that the targeting liposomes were selectively accumulated in the mitochondria, dissipating the mitochondrial membrane potential, opening the mitochondrial permeability transition pores, and releasing cytochrome C by translocation. This initiated a cascade of caspase 9 and 3 reactions and activated the pro-apoptotic Bax protein while suppressing the anti-apoptotic Mcl-1 protein, thereby enhancing the cytotoxic effect by acting on the mitochondrial signaling pathways. The efficacy in treating the drug-resistant A549cDDP xenografted tumor model after administration of the targeting lonidamine liposomes plus targeting epirubicin liposomes was the most significant compared with the administration of the controls at comparable doses. In conclusion, targeting lonidamine liposomes could be used as a potent co-therapy with an anticancer agent to enhance the efficacy of treating drug-resistant cancer by acting on the mitochondrial signaling pathways. (C) 2013 Elsevier Ltd. All rights reserved.