Transferrin-Conjugated Chitosan Nanoparticles for Direct Nose-to-Brain Delivery of Ziprasidone: Pharmacokinetic and Pharmacodynamic Evaluation

Ziprasidone (ZS) exhibits limited central nervous system (CNS) penetration due to the blood-brain barrier (BBB). This study investigated the pharmacokinetics and pharmacodynamics of ZS-loaded nanoparticles (NP) and transferrin-functionalized nanoparticles (Tf-NP) administered intravenously (IV) and intranasally (IN) in rats. Brain and plasma concentrations were quantified up to 24 h, and parameters including <i>C</i>_max, AUC_0-24, brain-to-plasma ratios, drug targeting efficiency (%DTE), and direct transport percentage (%DTP) were assessed. Behavioral assays evaluated antipsychotic efficacy. IN administration of NP and Tf-NP significantly enhanced brain exposure relative to IV and IN drug solution, with Tf-NP achieving the highest brain <i>C</i>_max (329.17 ± 19.79 ng/mL) and AUC_0-24 (4004.73 ± 396.87 ng·h/mL), and a %DTP exceeding 92%, indicative of effective nose-to-brain bypass of the BBB. Plasma exposure was reduced for NP and Tf-NP versus IV (<i>C</i>_max and AUC_0-∞), minimizing systemic side effects. Brain-to-plasma ratios markedly increased for NP (1.31) and Tf-NP (1.50) compared to IV (0.13). Tf-NP also elicited a faster onset and sustained pharmacodynamic response. These data demonstrate that intranasal Tf-functionalized ZS nanoparticles significantly improve CNS targeting and bioavailability while mitigating systemic exposure, supporting their development as targeted therapeutics for neuropsychiatric disorders.