The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer

• Published in: Biomaterials 2013-05, Vol.34 (14), p.3626-3638
• Main Authors: Zhou, Jia, Zhao, Wei-Yu, Ma, Xu, Ju, Rui-Jun, Li, Xiu-Ying, Li, Nan, Sun, Meng-Ge, Shi, Ji-Feng, Zhang, Cheng-Xiang, Lu, Wan-Liang
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Anticancer efficacy; Apoptosis - drug effects; Cell Line, Tumor; Cytochromes c; Dentistry; Drug Resistance, Neoplasm - drug effects; Female; Humans; Liposomes - chemistry; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Mice; Mice, Nude; Microscopy, Confocal; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial signaling pathway; Paclitaxel - chemistry; Paclitaxel - therapeutic use; Resistant lung cancer; Targeting paclitaxel liposomes; TPGS1000-TPP conjugate; Xenograft Model Antitumor Assays
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2013.01.078

Abstract Lung cancer is the leading cause of cancer-related death in humans and the multidrug resistance (MDR) is the major obstacle to successful chemotherapy of lung cancer. In this study, a d -α-tocopheryl polyethylene glycol 1000 succinate-triphenylphosphine conjugate (TPGS1000 -TPP) was synthesized as the mitochondrial targeting molecule, and was incorporated onto the surface of paclitaxel liposomes to treat the drug-resistant lung cancer. Evaluations were performed on the human lung cancer A549 cells, the drug-resistant lung cancer A549/cDDP cells, and the drug-resistant lung cancer A549/cDDP cells xenografted nude mice. The yield of TPGS1000 -TPP conjugate synthesized was about 50% and the particle size of targeting paclitaxel liposomes developed was approximately 80 nm. In comparison with taxol and regular paclitaxel liposomes, the targeting paclitaxel liposomes exhibited the strongest anticancer efficacy in vitro and in the drug-resistant A549/cDDP xenografted tumor model. The targeting paclitaxel liposomes could significantly enhance the cellular uptake, be selectively accumulated into the mitochondria, and cause the release of cytochrome C. This targeting delivery of drug initiated a cascade of caspase 9 and 3 reactions, activated the pro-apoptotic Bax and Bid proteins and suppressed the anti-apoptotic Bcl-2 protein, thereby enhancing the apoptosis by acting on the mitochondrial signaling pathways. In conclusion, the targeting paclitaxel liposomes have the potential to treat drug-resistant lung cancer.