Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response |
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| Affiliation: | 1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People''s Republic of China;2. National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People''s Republic of China;3. West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People''s Republic of China;1. Division of Gastroenterology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, Anhui 230001, PR China;2. School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China;3. Institutes for Life Sciences, School of Medicine, South China University of Technology, Guangzhou, Guandong 510006, PR China;4. The First Hospital and Institute of Immunology, Jilin University, Changchun 130061, PR China;1. School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand;2. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand;1. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China;2. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. Department of Chemical and Biomolecular Engineering, Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA |
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| Abstract: | 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-KLA-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 (∼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. |
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| Keywords: | Dual-functional liposome Mitochondria targeting pH response Paclitaxel Drug-resistant lung cancer Anticancer efficacy |
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