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 α-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 β-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. Cancer Res; 70(8); 3020-6. ©2010 AACR.

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma

“…We made use of this unique ability of CGKRK to reach the mitochondria by using the amphiphilic proapoptotic peptide D [KLAKLAK] 2 as the payload. D [KLAKLAK] 2 has been shown to act on mitochondria, the target of CGKRK (10), and several reports have described the antitumor activities of D [KLAKLAK] 2 (and some other peptides with similar activities), when selectively delivered to a target tissue (11)(12)(13)(14)(15)(27)(28)(29). The main limitation of these treatments has been that the D [KLA-KLAK] 2 peptide is highly toxic at the doses required for tumor treatment even with specific targeting.…”

Peptide Amphiphile Micelles Self-Adjuvant Group A Streptococcal Vaccination

“…They have been shown capable of delivering biologically active peptides for a variety of applications including angiogenesis (19,20), osteogenesis (21,22), neurogenesis (23,24), atherosclerosis treatment (25), cancer therapy (26,27), and islet transplantation (28,29). Also, peptide amphiphile micelles are comprised of a high concentration of peptide (30), inhibit peptide degradation (31), and can greatly increase peptide intracellular delivery (32).…”

Design and Modification of Anticancer Peptides

“…Standley et al [141] introduced a novel self-assembled nanoparticle that conjugated KLAK to Pas. It can kill the breast cancer cells not only by disrupting cell membrane, but also through the way of caspase independent and Bax/Bak independent apoptosis pathway.…”