Development and Evaluation of N-acetyl cysteine‑grafted Polyamidoamine Dendrimers for Enhanced Brain Delivery of Donepezil hydrochloride

Abstract

Donepezil hydrochloride (DPZ) is an 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 necessitates the use of ligand-mediated targeted delivery approaches for selective delivery to target site. This study reports synthesis and evaluation of N-acetyl cysteine (NAC)-conjugated 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 NAC-G4 conjugate, and percent drug entrapment, loading efficiency and release behavior were determined. Cell viability assay showed enhanced viability with DPZ on incorporation in the NAC-G4 conjugate. Further, we observed a higher peak plasma concentration, and mean residence time of DPZ from dendrimeric conjugate in pharmacokinetic studies. The DPZ-loaded ligand-conjugated dendrimeric conjugate holds promise as a potential strategy for the treatment of AD.