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.