Thiolated Chitosan Nanoparticles as a Promising Mucoadhesive Polymer in a Nose-to-Brain Delivery System: A Biodistribution Study in Mice

Delivering therapeutics to the brain is restricted by the blood-brain barrier (BBB). The intranasal route offers a non-invasive alternative to bypass the BBB, but its effectiveness is limited by rapid mucociliary clearance. To overcome this limitation, this study aimed to develop and characterize mucoadhesive thiolated chitosan (TCs) nanoparticles designed to prolong nasal residence time and facilitate nose-to-brain transport. Thiolated chitosan was synthesized, and its chemical modification was confirmed using Fourier-transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Nanoparticles from both TCs and unmodified chitosan (Cs) were then prepared by ionic gelation, incorporating Nile blue (NB) as a fluorescent probe. The synthesized TCs polymer showed a high degree of thiolation (491.38 ± 5.25 µmol/g). The resulting TCs nanoparticles had a mean particle size of 177.27 ± 4.14 nm, smaller than the Cs nanoparticles (229.03 ± 14.73 nm), with excellent entrapment efficiencies of 93.80% and 94.07%, respectively. In vivo biodistribution studies in male BALB/c mice revealed a prolonged nasal residence time of up to 6 hours for the TCs nanoparticles. Subsequent ex vivo analysis confirmed significantly higher accumulation of TCs nanoparticles in the nasal cavity compared to their Cs counterparts at 2 hours post-administration. Crucially, fluorescent signals originating from the TCs nanoparticle formulation were successfully detected in the brain. These findings demonstrate that thiolated chitosan nanoparticles are a potent mucoadhesive platform. By significantly increasing nasal residence time, this formulation enhances direct nose-to-brain delivery, presenting a promising strategy for transporting therapeutics to the central nervous system.