Aerosol-stable peptide-coated liposome nanoparticles: a proof-of-concept study with opioid fentanyl in enhancing analgesic effects and reducing plasma drug exposure.

Previously, we reported a novel pressurized olfactory drug (POD) delivery device that deposits aerosolized drug preferentially to upper nasal cavity. This POD device provided sustained central nervous system (CNS) levels of soluble morphine analgesic effects. However, analgesic onset of less soluble fentanyl was more rapid but brief, likely because of hydrophobic fentanyl redistribution readily back to blood. To determine whether fentanyl incorporated into an aerosol-stable liposome that binds to nasal epithelial cells will enhance CNS drug exposure and analgesic effects and reduce plasma exposure, we constructed Arg–Gly–Asp (RGD) liposomes anchored with acylated integrin-binding peptides (palmitoyl–Gly–Arg–Gly–Asp–Ser). The RGD liposomes, which assume gel phase membrane structure at 25°C, were stable under the stress of aerosolization as only 2.2 ± 0.5% calcein leakage was detected. The RGD-mediated integrin binding of liposome is also verified to be unaffected by aerosolization. Rats treated with fentanyl in RGD liposome and POD device exhibited greater analgesic effect, as compared with the free drug counterpart (AUCeffect = 1387.1% vs. 760.1% MPE*min), whereas approximately 20% reduced plasma drug exposure was noted (AUC0–120 = 208.2 vs. 284.8 ng min/mL). Collectively, fentanyl incorporated in RGD liposomes is physically and biologically stable under aerosolization, enhanced the overall analgesic effects, and reduced plasma drug exposure for the first 2 h. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2231–2239, 2014