Intranasal Administration of Acetaminophen-Loaded Poly(lactic-co-glycolic acid) Nanoparticles Increases Pain Threshold in Mice Rapidly Entering High Altitudes

<b>Background/Objectives:</b> Orally or intravenously administered acetaminophen experiences considerable liver first-pass elimination and may cause liver/kidney damage. This work examined the pharmacological effects of acetaminophen-loaded poly(lactic-<i>co</i>-glycolic acid) nanoparticles (AAP PLGA NPs) intranasally administered to mice rapidly entering high altitudes. <b>Methods:</b> AAP PLGA NPs were prepared using ultrasonication-assisted emulsification and solvent evaporation and characterized in terms of drug encapsulation efficiency and loading, in vitro and in vivo release behaviors, and toxicity to hippocampal neurons. In vivo fluorescence imaging was used to monitor the concentrations of AAP PLGA NPs (labeled with indocyanine green) in the brain and blood of the mice after intranasal administration. The effects of these NPs on the pain threshold in mice rapidly entering high altitudes were evaluated through hot plate and tail flick experiments. <b>Results:</b> The AAP PLGA NPs were found to be noncytotoxic, highly biocompatible and stable, with a drug encapsulation efficiency and loading capacity of 42.53% and 3.87%, respectively. The in vitro release of acetaminophen lasted for up to 72 h, and the release rate was ~82%. After intranasal administration in vivo, the drug release occurred slowly, and the drug was mainly concentrated in the brain. Compared with nonencapsulated acetaminophen, the intranasal administration of AAP PLGA NPs resulted in higher brain levels of the drug and delayed its elimination, thus increasing the pain threshold in mice rapidly entering high altitudes. <b>Conclusions:</b> The proposed strategy addresses the common problems of intranasal drug administration (low retention time and bioavailability) and paves the way for effective pain management in high-altitude environments.