Targeted Nose-to-Brain Delivery Using Functionalized Nanoparticles for Cognitive Restoration in Alzheimer's Disease

Alzheimer's disease (AD) represents the most prevalent and devastating form of age-related neurodegenerative disorder, characterized by progressive cognitive decline, memory impairment, and neuropsychiatric symptoms that arise from the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tau tangles, and chronic neuroinflammation. A major obstacle in the pharmacological management of AD is the inability of most therapeutic agents to cross the blood-brain barrier (BBB) in therapeutically meaningful concentrations following conventional systemic administration. The present investigation focuses on the design, fabrication, and comprehensive in vitro characterization of functionalized polymeric nanoparticles (NPs) loaded with Donepezil hydrochloride (DPZ), a first-line acetylcholinesterase inhibitor, intended for intranasal delivery as a novel cognitive restoration platform in Alzheimer's disease. Poly(lactic-co-glycolic acid) (PLGA) and chitosan were selected as the primary polymeric matrices and surface-functionalization agents, respectively, owing to their well-established biocompatibility, biodegradability, mucoadhesive properties, and ability to enhance cellular uptake. Eight distinct nanoparticle formulations (F1–F8) were systematically developed by varying PLGA concentration, chitosan coating levels, drug-to-polymer ratios, and the addition of stabilizers such as polyvinyl alcohol (PVA). The formulations were evaluated for particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE%), drug loading (DL%), in vitro drug release behavior using Franz diffusion cells, mucoadhesive strength, and ex vivo nasal permeation. Optimized formulations demonstrated particle sizes in the range of 145–310 nm, positive zeta potentials (due to chitosan coating), encapsulation efficiencies exceeding 72%, and sustained biphasic drug release profiles extending over 24 hours, with enhanced mucoadhesive properties suitable for prolonged olfactory epithelium contact time. The results demonstrate that chitosan-coated PLGA nanoparticles represent an effective and tunable platform for nose-to-brain delivery of antiAlzheimer drugs, with significant potential for advancing translational research in neurodegenerative disease therapy

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