Intranasal dalfampridine-loaded mucoadhesive polymeric nanoparticles for brain targeting: formulation and therapeutic evaluation in a cuprizone-induced demyelination model

Abstract:
The present study aimed to develop and comprehensively evaluate dalfampridine-loaded chitosan nanoparticles (DLM-CSNPs) for enhanced intranasal brain delivery in a cuprizone-induced demyelination model of multiple sclerosis (MS). The optimized nanoparticles were found to have a particle size of 166.5 nm with a small particle distribution (PDI 0.24), a positive surface charge (Zeta Potential +24.97 mV), and high entrapment efficiency (82%). Ex Vivo Permeation studies demonstrated that the permeation rate of the drug from DLM-CSNPs (902.26 µg/cm²) was significantly higher compared to the drug solution (609.96 µg/cm²). Histopathological studies confirmed the safety of the drug on the nasal mucosa. Sub-acute toxicity studies indicated the lack of significant systemic, hepatic, and renal toxicity of the compound after 28 days of repeated intranasal administration, even at a dose of 4 mg/kg. Pharmacokinetic studies indicated the better targeting of the brain by the intranasal route, where the brain C_max was two-fold higher, brain AUC 0-12 was significantly higher, brain T max was significantly lower, and the brain/plasma ratios were significantly higher compared to the oral route. When compared to the traditional oral route of administration, the intranasal DLM-CSNPs treatment has demonstrated improved delivery of the formulation to the central nervous system, functional recovery, decreased neuroinflammation, and neuroprotective effects, suggesting the therapeutic potential of the DLM-CSNPs formulation for the management of multiple sclerosis.