FORMULATION AND EVALUATION OF QUERCETIN-LOADED INTRANASAL NANOPARTICLES FOR NEUROPROTECTION AND ENHANCED BRAIN TARGETING IN ALZHEIMER'S DISEASE

Abstract

Alzheimer's disease (AD) represents a formidable neurodegenerative disorder characterized by complex pathophysiology involving amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation, with current therapeutic interventions offering only modest symptomatic relief. Quercetin, a naturally occurring flavonoid with potent multi-target neuroprotective properties, has emerged as a promising therapeutic candidate; however, its clinical translation is severely hampered by poor aqueous solubility, extensive first-pass metabolism, rapid elimination, and negligible blood-brain barrier permeability. This study aimed to develop and evaluate quercetin-loaded nanostructured lipid carriers (QT-NLCs) for intranasal administration to enhance brain targeting and neuroprotective efficacy in Alzheimer's disease. The formulation was optimized using Box-Behnken design, with the optimal composition comprising 5.2% w/w glyceryl monostearate, 2.8% w/w oleic acid, 3.5% w/w Tween 80, and a drug-to-lipid ratio of 1:10, prepared by high-pressure homogenization followed by ultrasonication. The optimized QT-NLCs exhibited a mean particle size of 128.4 ± 4.2 nm, polydispersity index of 0.194 ± 0.021, zeta potential of -32.6 ± 2.8 mV, entrapment efficiency of 87.3 ± 3.1%, and drug loading of 8.7 ± 0.4%. In vitro drug release demonstrated biphasic sustained release with 78.4 ± 3.6% cumulative release at 72 hours, following Korsmeyer-Peppas kinetics (R² = 0.982). Ex vivo nasal permeation studies revealed 2.3-fold enhanced permeation flux (2.84 ± 0.21 µg/cm²/h) and significantly improved mucoadhesion with residence time of 4.2 ± 0.5 hours. In vitro cytotoxicity assays using PCS-200-014 neuronal cells demonstrated reduced cytotoxicity (IC50 = 124.6 ± 8.7 µg/mL) and 3.5-fold higher cellular uptake for QT-NLCs compared to free quercetin. In vivo pharmacokinetic studies in Wistar rats following intranasal administration demonstrated significantly enhanced brain targeting with drug targeting efficiency of 342.6% and drug targeting percentage of 72.8%, indicating preferential brain delivery. Pharmacodynamic evaluation in trimethyltin-induced neurodegeneration model revealed significant cognitive improvement (42.8% reduction in escape latency, 38.6% increase in recognition index), reduction in oxidative stress (SOD: +38.7%, GSH: +42.3%, MDA: -51.2%), and attenuation of neuroinflammation. Histopathological and immunohistochemical analyses confirmed reduced neuronal damage, glial activation, amyloid-β plaque deposition, and phosphorylated tau expression. These findings demonstrate that intranasal administration of QT-NLCs offers a promising strategy to overcome quercetin's bioavailability limitations, achieving effective brain targeting and multi-target neuroprotective efficacy, positioning this formulation as a potential therapeutic candidate for Alzheimer's disease management. The study provides a robust foundation for further translational research toward clinical application, though additional long-term safety and efficacy studies are warranted.