Regulating Peptide Amphiphile Micelle Properties Via Lipid Content for Drug Delivery Applications

Current cancer treatments are well known for their considerable cytoxicity and undesirable off-target effects. To address these significant shortcomings, new classes of therapeutics need to be developed to improve treatment efficacy and patient comfort. Peptide-based therapeutics are a promising alternative to traditional chemotherapies, but in vivo delivery of peptides is challenging due to their low membrane permeability, loss of secondary structure, and low local therapeutic concentration. Conjugating hydrophilic peptides comprised of therapeutics and bioactivity modulating components (e.g., cell penetrating peptides – CPPs) with hydrophobic lipid tails yields modular peptide amphiphiles (PAs). These PAs self-assemble in water to form micelle nanoparticles (PAMs) when at high enough concentrations by hiding their hydrophobic lipid components in their cores and displaying their hydrophilic peptide components on their surface. Excitingly, micelle-mediated delivery of peptide therapeutics can address many, if not all, of the primary concerns associated with free peptide delivery. While promising, most work to date with PAs focuses on the use of only a small number of lipid moieties, primarily focusing on using one or more palmitic acids. To expand the number of PAs available, this work focuses on exploring the impact that altering lipid chain length, number of desaturation events, and equivalents of lipids per peptide has on PAM size, shape, and stability. As a test bed for this effort, novel PAs were explored for their capacity to alter the bioactivity of a therapeutic peptide that has shown broad-spectrum anti-neoplastic effects in hematological cancer. Specifically, PAM physical and biological characteristics were studied in vitro employing a human B cell leukemia to determine the impact lipid tail size has on desirable PAM cancer cell cytotoxicity. Based on this work, lipids can be selectively chosen to optimize material characteristics for drug delivery applications of PAMs not only for cancer therapy but also a wide variety of other drug delivery applications.