Development of Biodegradable Polymeric Nanoparticle-Based Drug Delivery Systems for Targeted Brain Delivery of Antiepileptic Drugs Across the Blood-Brain Barrier

Epilepsy affects approximately 3.5 million people in Nigeria, with uncontrolled seizures disproportionately prevalent in patients without access to consistent antiepileptic drug therapy. A fundamental pharmacological challenge limiting antiepileptic drug efficacy is poor penetration of the blood-brain barrier, necessitating high systemic doses associated with adverse effects. This study developed and evaluated PLGA-based polymeric nanoparticles functionalised with transferrin receptor-targeting peptides for enhanced brain-targeted delivery of carbamazepine. Nanoparticles were prepared by nanoprecipitation and characterised for size, zeta potential, encapsulation efficiency, surface ligand density, and in vitro release. Transferrin receptor-mediated cellular uptake was assessed in hCMEC/D3 brain endothelial cells. In vitro BBB transport was modelled using a co-culture Transwell system of hCMEC/D3 and astrocytes. In vivo brain distribution was evaluated in Sprague-Dawley rats by LC-MS/MS quantification of carbamazepine in brain and plasma compartments following intravenous administration. Targeting efficiency was compared between functionalised and non-functionalised nanoparticles and free carbamazepine solution. Functionalised nanoparticles demonstrated 3.4-fold higher brain accumulation than non-targeted nanoparticles and 5.8-fold higher than free drug. Seizure suppression in a pentylenetetrazole-kindling rat model was significantly prolonged for the targeted nanoparticle formulation at 50% of the conventional therapeutic dose. These results provide original data supporting transferrin-targeted PLGA nanoparticles as a viable strategy for antiepileptic drug brain targeting with potential to reduce dose-related adverse effects. Keywords: PLGA nanoparticles, blood-brain barrier, carbamazepine, targeted drug delivery, antiepileptic.