Ondansetron-loaded magnetically targeted nanocarriers for anxiety: optimization, in vitro characterization, and in...

This study investigated an intranasal nose-to-brain delivery strategy to repurpose ondansetron (OND) for anxiety management using PLGA nanoparticles co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and incorporated into a Carbopol 940 mucoadhesive gel. Nanoparticles were optimized using an I-optimal experimental design evaluating PLGA concentration and surfactant type. The optimized SPION/OND-PLGA nanoparticles showed a small particle size (141.547 ± 1.31 nm), narrow size distribution (PDI = 0.235 ± 0.002), relatively high zeta potential (-34.307 ± 0.53 mV), and satisfactory encapsulation efficiency (42.09 ± 1.34%). The developed nanogel exhibited acceptable organoleptic properties, shear-thinning behavior, sustained drug release, and enhanced ex vivo nasal permeability, with OND permeation values of 996.96 ± 6.53 μg, 621.92 ± 7.54 μg, and 317.87 ± 2.88 μg per cm² within 6 h for the nanogel,SPION/PLGA NPs and aqueous solution, respectively. In vivo behavioral studies (open field test and elevated plus maze) demonstrated significant anxiolytic activity in all OND-treated groups, with superior efficacy for the magnetically targeted nanogel. Neurochemical and biochemical analysis indicated a monoaminergic-dominant anxiolytic profile, increased BDNF expression, and improved oxidative stress status. Molecular docking revealed strong OND binding to 5-HT5A and 5-HT3A receptors. Overall, magnetic intranasal nanocarriers substantially enhanced the anxiolytic and neuroprotective efficacy of ondansetron.