Coassembled Cytotoxic and Pegylated Peptide Amphiphiles Form Filamentous Nanostructures with Potent Antitumor Activity in Models of Breast Cancer
Self-assembled peptide amphiphiles (PAs) consisting of hydrophobic, hydvrogen-bonding, and charged hydrophilic domains form cylindrical nanofibers in physiological conditions and allow for the presentation of a high density of bioactive epitopes on the nanofiber surface. We report here on the use of PAs to form multifunctional nanostructures with tumoricidal activity. The combination of a cationic, membrane-lytic PA coassembled with a serum-protective, pegylated PA was shown to self-assemble into nanofibers. Addition of the pegylated PA to the nanostructure substantially limited degradation of the cytolytic PA by the protease trypsin, with an 8-fold increase in the amount of intact PA observed after digestion. At the same time, addition of up to 50% pegylated PA to the nanofibers did not decrease the in vitro cytotoxicity of the cytolytic PA. Using a fluorescent tag covalently attached to PA nanofibers we were able to track the biodistribution in plasma and tissues of tumor-bearing mice over time after intraperitoneal administration of the nanoscale filaments. Using an orthotopic mouse xenograft model of breast cancer, systemic administration of the cytotoxic pegylated nanostructures significantly reduced tumor cell proliferation and overall tumor growth, demonstrating the potential of multifunctional PA nanostructures as versatile cancer therapeutics.