Fan_2023_Eur.J.Pharm.Sci__106406

PURPOSE: Organophosphorus compounds (OPs) is a serious threat to human health and life safety, but because of the existence of blood-brain barrier, most of the therapeutic drugs can not enter the center, reactivate centrally located toxic acetylcholinesterase (AChE), it is urgent to find an efficient treatment method. METHODS: The c(RGDyK) cyclic peptide modified HI-6-loaded brain targeting liposomes [c(RGDyK)-PEG(2000)-HI-6-lipo] were prepared by ammonium sulfate gradient method. The in vitro blood-brain barrier (BBB) model was established, and the function of the liposomes was evaluated. The animal model of DDVP poisoning was established, and the central toxic enzyme reactivation ability of c(RGDyK)-PEG(2000)-HI-6-lipo by both the intravenous and nasal administration route was verified. RESULTS: The HI-6-loaded liposomes with brain targeting function were successfully synthesized and prepared with high encapsulation efficiency (70.23 +/- 2.18%), drug loading (2.86 +/- 0.07)%, average particle size 242.9 nm (polydispersion index 0.149), and potential -16.2 mV. Combined with the in vitro and in vivo studies, the c(RGDyK)-PEG(2000)-HI-6-lipo has better ability to cross the BBB. In addition, compared with intravenous injection, nasal administration was proved to be more effective against organophosphorus poisoning, and the reactivation rate of brain acetylcholinesterase reached (26.19 +/- 7.70)%. CONCLUSION: The prepared c(RGDyK)-PEG(2000)-HI-6-lipo has a better ability to cross BBB. Nasal administration, as a way to bypass the BBB and directly deliver drugs into the brain, effectively improves the bioavailability of HI-6 in the brain. This study holds promise by providing a non-invasive approach to deliver water-soluble oxime antidote into the brain and reactivate central acetylcholinesterase via the naso-brain route.