Aerosol-Stable Peptide-Coated Liposome Nanoparticles: A Proof-of-Concept Study with Opioid Fentanyl in Enhancing Analgesic Effects and Reducing Plasma Drug Exposure

Abstract

Previous we reported a novel pressurized olfactory drug (POD) delivery device that deposit aerosolized drug preferentially to upper nasal cavity. This POD device provided sustained CNS levels of soluble morphine analgesic effects. However, analgesic onset of less soluble fentanyl was more rapid but brief, likely due to 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 RGD liposomes anchored with acylated integrin binding peptides (palmitoyl-GRGDS). 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 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, compared to the free drug counterpart (AUCeffect = 1387.l vs. 760.1 %MPE*min); while ~20% reduced plasma drug exposure was noted (AUC0-120 = 208.2 vs 284.8 ng*min/ml). Collectively, fentanyl incorporated in RGD-liposomes are physically and biologically stable under aerosolization, enhanced the overall analgesic effects and reduced plasma drug exposure for the first 2 hours.

Endothelial Cell Targeting by cRGD-Functionalized Polymeric Nanoparticles under Static and Flow Conditions

“…Cell association of NPs was also highly influenced by the surface density of cRGD. Similarly, other research groups have found that increasing RGD-densities on the surface of nanocarriers generally result in increasing binding to the integrin α v β 3 , coated on plate surfaces or present on the surface of cells [ 64 , 65 ]. In the present work, the NPs association to HUVECs increased with increasing RGD-densities and reached a maximum at ~118,000 RGD/µm 2 (density on the high cRGD-NPs).…”

Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting

“…Interestingly, when the liposomes were administered to rats using the POD device, fentanyl plasma concentrations as well as those measured in the brain 5 min post-administration were lower than those obtained using free fentanyl (although not significantly different). However, when the analgesic effect was measured, the fentanyl-loaded RGD liposomes provided a slightly slower onset of action and a lower, but more prolonged, analgesic effect [ 175 ]. The decision to use in small animals a device optimized for deposition in the human nasal cavity is questionable.…”

Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses

“…Nanoparticles have attracted interest in recent years because these systems act as carriers providing controlled and sustained drug delivery and increasing the drug's bioavailability and mean residence time (Sukhorukov et al, 2005). The pharmacodynamics and pharmacokinetics of nanoparticulated opioids administered by several routes, including orally, have been investigated in numerous species (Mystakidou et al, 2007;Paul-Murphy et al, 2009;Wang et al, 2009;Krugner-Higby et al, 2011;Hoekman et al, 2014;Han et al, 2015;Vazzana et al, 2015). However, to our knowledge, there are no studies reporting the possible antinociceptive effect of methadone administered orally to horses, as free drug or as nanoencapsulated formulation.…”