Double-layered nano vesicular chitosan-coated liposomal system loaded with donepezil cargo for Alzheimer's disease:...

Alzheimer's disease (AD) is a progressive neurological disorder impacting cognition. Donepezil (DZ), an acetylcholinesterase inhibitor, is often prescribed but has poor brain bioavailability due to the blood-brain barrier (BBB) and first-pass metabolism. This work aims primarily to develop a chitosan-coated phosphatidylcholine liposome formulation to improve DZ delivery to the brain and bypass the BBB. Secondary goals include a thorough characterization of this formulation. Phosphatidylcholine was selected for its biocompatibility and ability to form stable liposomes. Chitosan was chosen to coat these liposomes due to its permeation-enhancing properties, while Tween was included to improve formulation stability and enhance drug encapsulation. Using a robust Box-Behnken design, DZ-loaded liposomes were optimized and characterized for size, stability, and safety. The potential of nanoparticles to deliver their cargo to the brain was assessed through qualitative and quantitative cellular uptake assays using the human endothelial cell line ECV-304, as well as through an in vivo study in mice. The statistically optimized loaded vesicles had the smallest globule size (74.86 ± 2.3 nm) and acceptable physicochemical characteristics. Notably, the coated liposomal formulations showed a safe profile at concentrations up to and below 62.5 μg/ml, a threshold included here for clarity regarding biocompatibility. The liposomal systems demonstrated effective cellular uptake, with the chitosan-coated formulations showing superiority, achieving a 66.8 ± 10.6 % uptake rate. This work addresses a critical gap by being the first to optimize chitosan-coated phosphatidylcholine liposomes specifically for the transport of DZ, highlighting its translational potential as a sustainable, affordable, and effective strategy for Alzheimer's therapy.