Design, In Silico Targeting, and Characterization of Curcumin-Ibuprofen Prodrug Microspheres for Brain-Specific Delivery in Alzheimer's Therapy.

Abstract

Introduction: Alzheimer's Disease (AD) is a complex neurodegenerative condition characterized by limited treatment effectiveness, attributed to inadequate Blood-Brain Barrier (BBB) permeability and low medication absorption. Curcumin and ibuprofen possess anti-inflammatory and neuroprotective properties but are limited by pharmacokinetic constraints. This study aimed to synthesize a curcumin-ibuprofen mutual prodrug (CIP), formulate it into chitosan-based microspheres (CIPM), and evaluate its neuroprotective potential for brain-targeted delivery in AD.

Methods: CIP was synthesized via ethylenediamine carbodiimide (EDCI) mediated esterification and confirmed through IR, NMR, LC-MS, and DSC. CIPM microspheres were prepared using emulsion crosslinking, characterized by scanning electron microscopy, drug entrapment efficiency (85.5%), zeta potential, particle size analysis, and DSC. In silico tools (SwissADME, ProTox-II) and molecular docking were used to assess ADMET profiles and target binding (AChE, BACE1, β-secretase). Network pharmacology identified overlapping targets between curcumin and AD. In vivo evaluation was conducted in a TMT (Trimethyltin)- induced neurodegeneration rat model through behavioral Morris Water Maze (MWM), Novel Object Recognition (NOR), Social Recognition Test (SRT), and biochemical and histological assessments.

Results: CIP demonstrated strong binding affinity with AD-related targets (-10.0 to -8.5 kcal/mol) and favorable ADMET properties. Network analysis identified 226 overlapping targets and key hub genes. CIPM significantly improved cognitive performance, antioxidant enzyme levels, and neuronal integrity compared to individual drugs and showed comparable efficacy to donepezil.

Discussion: The present study demonstrates that the curcumin-ibuprofen conjugate, when delivered through chitosan-based microspheres, effectively enhances brain targeting and overcomes pharmacokinetic barriers. The formulation not only improved drug bioavailability but also showed superior neuroprotective and cognitive benefits compared to individual drugs. Molecular docking and network pharmacology further confirmed its multi-target potential, suggesting a synergistic mechanism in modulating key AD pathways. These outcomes highlight CIPM as a promising candidate that warrants further pharmacokinetic and clinical validations for Alzheimer's therapy.

Conclusion: The curcumin-ibuprofen prodrug-loaded microspheres present a promising brain-targeted treatment approach for Alzheimer's disease by improving bioavailability, engaging multiple targets, and providing neuroprotection.