(746b) Self-Assembled Peptide-Amphiphile/Lipid Mixtures

Peptide-amphiphiles (PAs) can self-assemble into a variety of lamellar and non-lamellar structures depending on their chemical structures, surface activities, and molecular packing parameters. When bioactive amino acids are employed, these structures can serve as therapeutic agents and delivery vehicles. To facilitate the assembly of cationic vesicle structures, we have synthesized PAs using solid phase Fmoc chemistry that contain cationic amino acid headgroups linked to two hydrocarbon tails. The base structure of these peptides is NH(X)-Lys(acyl)-Arg-Lys(acyl)-COOH were X at the amino terminal is adjusted to control headgroup charge and lipid-lipid interactions, and the acyl groups are adjusted to control tail length, bilayer thickness, and hydrophobic interactions. Mixing PAs at different ratios with a zwitterionic lipid, such as dipalmitoylphosphatidylcholine (DPPC), is used to control vesicle size and surface charge density. Using a PA with X as an acetyl group (-COCH₃), cryogenic transmission electron microscopy (cryo-TEM) has revealed variations in the morphology of PA/DPPC assemblies. Increasing PA concentration from 25 to 100% led to morphological transitions from cylindrical (80-100 nm in diameter, up to 1000 nm in length) to spherical vesicles (50 to 100 nm) and then spherical vesicles to micelles. Fluorescence anisotropy studies using diphenylhexatriene (DPH) indicated that the addition of PA led to a decrease in the bilayer melting temperature, from 42 °C (pure DPPC) to 37.5 °C PA, and a broad melting region from approximately 35 to 45 °C. The melting region includes physiological temperature, which suggests that cationic PA/DPPC assemblies could potentially be used for drug delivery applications.