Design and Characterization of a Multifunctional pH-Triggered Peptide C8 for Selective Anticancer Activity

• Published in: Advanced healthcare materials 2015-12, Vol.4 (17), p.2709-2718
• Main Authors: Lu, Sheng, Bennett, W. F. Drew, Ding, Yong, Zhang, Lei, Fan, Helen Y., Zhao, Danyang, Zheng, Tao, Ouyang, Ping-Kai, Li, Jason, Wu, Yan, Xu, Wen, Chu, Dafeng, Yuan, Yongfang, Heerklotz, Heiko, Karttunen, Mikko, Chen, P.
• Format: Article
• Language: English
• Subjects: Animals; anticancer peptides; Antineoplastic Agents - chemistry; Cancer; Carriers; Carriers, Drug; Cell Line, Tumor; cell specificity; Drug Carriers - chemistry; drug delivery; Drug delivery systems; Drug Delivery Systems - methods; Drugs; Ellipticines - chemistry; Histidine - chemistry; Humans; Hydrogen-Ion Concentration; Liposomes - chemistry; Mice; nanofibers; Nanostructure; Nanostructures - chemistry; NIH 3T3 Cells; Peptides; Peptides - chemistry; pH-responsiveness; Self assembly; Strategy
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.201500636

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. A multifunctional cationic lytic peptide is designed incorporating amino acid pairing, amphipathic structure, and histidine‐mediated pH‐sensitivity for controllable membrane lytic activity and nanostructure. The peptide can deliver small‐molecule drugs in a pH‐triggered manner with selectively enhanced synergetic anticancer activity, which originates from the selective lytic activity of the peptide, representing a novel therapeutic carrier strategy.