Suthar_2025_Mol.Pharm__

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by dementia and cognitive impairments. Acetylcholinesterase (AChE) inhibitors are generally prescribed for clinical management of AD symptoms. Donepezil hydrochloride (DPZ) is a reversible, selective, and noncompetitive inhibitor of AChE recommended for the treatment of mild-to-moderate AD. However, a higher dose of this drug must be administered to achieve adequate therapeutic concentrations in the brain, leading to peripheral side effects. In the present research work, oleic acid (OA) conjugated PAMAM G4 dendrimers (OA-G4) are explored for delivering DPZ to the brain. OA was conjugated to PAMAM G4 dendrimers using EDC conjugation chemistry, and the conjugation was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopy. DPZ was successfully loaded on the OA-G4 conjugate, and the loading and entrapment efficiency were found to be 78.59% +/- 5.52% and 62.12% +/- 0.67%, respectively. The drug release studies showed a faster release of DPZ from the DPZ-OA-G4 conjugate for the initial 6 h, followed by a sustained release, with 68.44% +/- 1.88% of the drug released in 24 h. Cytotoxicity studies in SH-SY5Y cells demonstrated the safety and cytocompatibility of the conjugate at a wide range of concentrations. Cell internalization study revealed deep localization of the dendrimeric nanoconjugate in SH-SY5Y cells. Biodistribution studies of the OA-G4 conjugate through the intranasal route, using an IVIS whole-body live imaging system, demonstrated abundant fluorescence in the brain, indicating efficient brain targeting via nose-to-brain delivery. Neurobehavior studies in male SD rats suggested significant attenuation of AlCl(3)-induced cognitive decline in DPZ-OA-G4 treated animals, which was further confirmed with biochemical and histological evaluations. In conclusion, this study provides proof of concept that DPZ can be successfully targeted to the brain using ligand-conjugated dendrimeric systems via intranasal administration, a noninvasive route that enables direct nose-to-brain delivery, bypasses the blood-brain barrier, and minimizes systemic side effects.