title: Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide.
abstract: Nanotechnology offers novel delivery vehicles for cancer therapeutics. Potential advantages of nanoscale platforms include improved pharmacokinetics, encapsulation of cytotoxic agents, enhanced accumulation of therapeutics in the tumor microenvironment, and improved therapeutic structures and bioactivity. Here, we report the design of a novel amphiphilic molecule that self-assembles into nanostructures for intracellular delivery of cytotoxic peptides. Specifically, a cationic alpha-helical (KLAKLAK)(2) peptide that is known to induce cancer cell death by membrane disruption was integrated into a peptide amphiphile (PA) that self-assembles into bioactive, cylindrical nanofibers. PAs are composed of a hydrophobic alkyl tail, a beta-sheet forming peptide, and a bioactive peptide that is displayed on the surface of the nanofiber after self-assembly. PA nanostructures that included (KLAKLAK)(2) were readily internalized by breast cancer cells, in contrast to the (KLAKLAK)(2) peptide that on its own was not cell permeable. (KLAKLAK)(2) nanostructures, but not the peptides alone, also induced breast cancer cell death by caspase-independent and Bax/Bak-independent mechanisms associated with membrane disruption. Significantly, (KLAKLAK)(2) nanostructures induced cell death more robustly in transformed breast epithelial cells than in untransformed cells, suggesting a degree of tumor selectivity. Our results provide proof-of-principle that self-assembling PAs can be rationally designed to generate nanostructures that can efficiently deliver cytotoxic peptides to cancer cells.
authors.affiliation: Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Institute for BioNanotechnology in Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Stephany M
authors.initials: SM
authors.lastname: Standley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Toft
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.forename: Stephen
authors.initials: S
authors.lastname: Soukasene
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Srikumar M
authors.initials: SM
authors.lastname: Raja
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
authors.forename: Samuel I
authors.initials: SI
authors.lastname: Stupp
mesh_terms: D000818:Animals; D002412:Cations; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D018613:Microscopy, Confocal / Q000379:methods; D049329:Nanostructures / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D009369:Neoplasms / Q000473:pathology* / Q000628:therapy*; D010455:Peptides / Q000737:chemistry
chemical_list: D002412:Cations; D010455:Peptides