TY - JOUR
T1 - Design and characterization of a multifunctional pH-triggered peptide C8 for selective anticancer activity
AU - Lu, S.
AU - Bennett, W.F.D.
AU - Ding, Y.
AU - Zhang, L.
AU - Fan, H.Y.
AU - Zhao, D.
AU - Zheng, T.
AU - Ouyang, P.K.
AU - Li, J.
AU - Wu, Y.
AU - Xu, Wen
AU - Chu, D.
AU - Yuan, Y.
AU - Heerklotz, H.
AU - Karttunen, M.
AU - Chen, P.
PY - 2015/12/9
Y1 - 2015/12/9
N2 - 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.
AB - 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.
KW - Anticancer peptides
KW - Cell specificity
KW - Drug delivery
KW - Nanofibers
KW - PH-responsiveness
UR - http://www.scopus.com/inward/record.url?scp=84954370863&partnerID=8YFLogxK
U2 - 10.1002/adhm.201500636
DO - 10.1002/adhm.201500636
M3 - Article
C2 - 26474414
AN - SCOPUS:84954370863
SN - 2192-2640
VL - 4
SP - 2709
EP - 2718
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 17
ER -
