Comparative evaluation of donepezil-loaded polymeric and liposomal nanoparticles for Alzheimer's disease: biocompatibility, drug release kinetics, and cellular uptake study

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition that accounts for approximately 65% of all dementia cases worldwide. Donepezil (DNP) is an acetylcholinesterase inhibitor that is widely prescribed for AD patients. However, extensive first-pass metabolism and the presence of the blood–brain barrier (BBB) significantly restrict its therapeutic efficacy. To address these challenges, two nanocarrier systems were developed: biodegradable polycaprolactone (PCL) and polyvinyl alcohol (PVA)-based polymeric nanoparticles, and dipalmitoylphosphatidylcholine (DPPC)-based liposomes. DNP-loaded PCL/PVA double emulsion nanoparticles and DPPC liposomes were prepared and characterized based on their particle sizes, uniformity, zeta potential, entrapment efficiency, Fourier transform infrared spectroscopy (FTIR), and in vitro drug release kinetics. Their safety profiles and cellular uptake potential were evaluated using the trypan blue exclusion assay and qualitative and quantitative cellular uptake assays with the human endothelial-like ECV-304 and neuronal PC-12 cell lines. The mean particle sizes of polymeric nanoparticles and liposomes were 175.97 ± 11.72 nm and 115.18 ± 4.63 nm, respectively, with low polydispersity indices (<0.3) and negative zeta potentials. FTIR analysis confirmed the absence of chemical interactions between DNP and formulation components. In addition, both nanocarrier systems demonstrated favorable biocompatibility, with cell viability exceeding 80%. Liposomes exhibited a more controlled drug release profile over 48 hours compared to polymeric nanoparticles. In contrast, both formulations exhibited significantly higher cellular uptake compared to their respective controls, with polymeric nanoparticles showing significantly higher cellular uptake than liposomes in ECV-304 cells (27.41 ± 2.38%, p < 0.05), demonstrating that carrier composition is a key determinant of nanoparticle–cell interactions independent of targeting ligands or surface modifications. This suggests that polymeric nanoparticles enhance in vitro cellular uptake in endothelial-like cells, warranting further in vivo investigation for their brain delivery potential.