title: Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response.
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.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China. Electronic address: li_li@scu.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: He
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Qiangying
authors.initials: Q
authors.lastname: Yi
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China.
authors.forename: Weisan
authors.initials: W
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People's Republic of China; National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China. Electronic address: zwgu@scu.edu.cn.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D011522:Protons
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D010455:Peptides; D010714:Phosphatidylethanolamines; D011522:Protons; C038089:1,2-distearoylphosphatidylethanolamine; D045304:Cytochromes c; D053453:Caspase 9; D017239:Paclitaxel
keywords: Anticancer efficacy; Drug-resistant lung cancer; Dual-functional liposome; Mitochondria targeting; Paclitaxel; pH response