Development and evaluation of N-acetyl cysteine-grafted polyamidoamine dendrimers for enhanced brain delivery of donepezil hydrochloride

Abstract

Donepezil hydrochloride (DPZ) is a USFDA-approved, selective and non-competitive, centrally acting acetylcholinesterase inhibitor used for the clinical management of dementia associated with mild-to-moderate Alzheimer's disease (AD). However, treatment with DPZ is usually associated with various peripheral adverse effects, which necessitate the use of ligand-mediated targeted delivery approaches for selective delivery to the target site. This study reports the synthesis and evaluation of N-acetyl cysteine (NAC)-conjugated poly(amidoamine) G4 (PAMAM G4) dendrimers for brain-targeted delivery of DPZ. Fourier-transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy were used to confirm the conjugation of NAC to PAMAM G4 dendrimers. DPZ was loaded onto PAMAM G4 and the NAC-G4 conjugate, and % drug entrapment, loading efficiency, and release behavior were determined. The cell viability assay showed enhanced viability with DPZ on incorporation into the NAC-G4 conjugate. Furthermore, we observed a higher peak plasma concentration and mean residence time of DPZ from the dendrimeric conjugate in pharmacokinetic studies. The DPZ-loaded ligand-conjugated dendrimeric conjugate holds promise as a potential strategy for the treatment of AD.