title: Design and Characterization of a Multifunctional pH-Triggered Peptide C8 for Selective Anticancer Activity.
abstract: Most drug delivery systems have been developed for efficient delivery to tumor sites via targeting and on-demand strategies, but the carriers rarely execute synergistic therapeutic actions. In this work, C8, a cationic, pH-triggered anticancer peptide, is developed by incorporating histidine-mediated pH-sensitivity, amphipathic helix, and amino acid pairing self-assembly design. We designed C8 to function as a pH-responsive nanostructure whose cytotoxicity can be switched on and off by its self-assembly: Noncytotoxic β-sheet fibers at high pH with neutral histidines, and positively charged monomers with membrane lytic activity at low pH. The selective activity of C8, tested for three different cancer cell lines and two noncancerous cell lines, is shown. Based on liposome leakage assays and multiscale computer simulations, its physical mechanisms of pore-forming action and selectivity are proposed, which originate from differences in the lipid composition of the cellular membrane and changes in hydrogen bonding. C8 is then investigated for its potential as a drug carrier. C8 forms a nanocomplex with ellipticine, a nonselective model anticancer drug. It selectively targets cancer cells in a pH-responsive manner, demonstrating enhanced efficacy and selectivity. This study provides a novel powerful strategy for the design and development of multifunctional self-assembling peptides for therapeutic and drug delivery applications.
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, 200 University Avenue West, Ontario, N2L 3G1, Canada.
authors.forename: W F Drew
authors.initials: WF
authors.lastname: Bennett
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.|College of Biological and Pharmaceutical Engineering, Nanjing University of Technology, 30 Puchu Road South, Nanjing, Jiangsu, 211816, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
authors.forename: Helen Y
authors.initials: HY
authors.lastname: Fan
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Danyang
authors.initials: D
authors.lastname: Zhao
authors.affiliation: College of Biological and Pharmaceutical Engineering, Nanjing University of Technology, 30 Puchu Road South, Nanjing, Jiangsu, 211816, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: College of Biological and Pharmaceutical Engineering, Nanjing University of Technology, 30 Puchu Road South, Nanjing, Jiangsu, 211816, China.
authors.forename: Ping-Kai
authors.initials: PK
authors.lastname: Ouyang
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 227 Chongqing Road South, Shanghai, 201999, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Dafeng
authors.initials: D
authors.lastname: Chu
authors.affiliation: Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 227 Chongqing Road South, Shanghai, 201999, China.
authors.forename: Yongfang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.|Institute for Pharmaceutical Sciences, Albert-Ludwigs University of Freiburg, Hermann-Herder Str. 9, 79104, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Heerklotz
authors.affiliation: Department of Chemistry and Waterloo Institute for Nanotechnology, University of Waterloo, Waterloo, 200 University Avenue West, Ontario, N2L 3G1, Canada.|Department of Mathematics and Computer Science and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, MetaForum, 5600, MB, Eindhoven, The Netherlands.
authors.forename: Mikko
authors.initials: M
authors.lastname: Karttunen
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004611:Ellipticines / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D041681:NIH 3T3 Cells; D049329:Nanostructures / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D004611:Ellipticines; D008081:Liposomes; D010455:Peptides; C034192:ellipticine; D006639:Histidine
keywords: anticancer peptides; cell specificity; drug delivery; nanofibers; pH-responsiveness