title: Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides.
abstract: Mitochondria serve as both "energy factories" and "suicide weapon stores" of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity.
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu.
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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Ethan Michael
authors.initials: EM
authors.lastname: Gerhard
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu, Sichuan.
authors.forename: Xuehua
authors.initials: X
authors.lastname: Jiang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism; D041681:NIH 3T3 Cells; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000972:Antineoplastic Agents, Phytogenic; D036341:Intercellular Signaling Peptides and Proteins; C535058:KLA peptide; D008081:Liposomes; D010455:Peptides; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel
keywords: antiangiogenesis; anticancer; mitochondria; multistage tumor-targeting liposome; paclitaxel