Transferrin-Conjugated Chitosan Nanoparticles for Direct Nose-to-Brain Delivery of Ziprasidone: Pharmacokinetic and Pharmacodynamic Evaluation
Teja Kumar Ponduri, Chakravarthi Guntupalli, Balamurugan Jeganathan, Narender Malothu, Swetha Kowtharapu
Abstract
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 C 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 C 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 ( C 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.