Design and Biological Evaluation of Lipoprotein-Based Donepezil Nanocarrier for Enhanced Brain Uptake through Oral Delivery.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory and cognitive impairment. Donepezil is an acetylcholinesterase inhibitor used for the symptomatic treatment of AD. However, high dose of donepezil is prescribed to achieve effective concentration in the brain, which leads to significant side effects gastrointestinal alterations and hepatotoxicity. In the present study, ApoE3 conjugated polymeric nanoparticles derived from di-block copolymer methoxy poly(ethyleneglycol)-polycaprolactone (mPEG-PCL) have been used to boost the delivery of donepezil to the brain. mPEG-PCL is an amphiphilic di-block polymer with a tendency to avoid nanoparticle uptake by phagocytic cells in the liver and can significantly reduce the gastric mucosal irritations. Moreover, ApoE3 based nanocarriers showed a promising ability to enhance brain uptake, binding to amyloid beta with high affinity and accelerating its clearance. Donepezil loaded polymeric nanoparticles was performed by using nanoprecipitation method, further surface modified with polysorbate 80 and ApoE3 to increase the brain bioavailability and reduce the dose. Optimization of various process parameters were performed using quality by design approach. ApoE3 polymeric nanoparticles were found to be stable in simulated gastric fluids and exhibited sustained drug release pattern. Cellular uptake studies conformed better neuronal uptake of the developed formulation, which is further corroborated with pharmacokinetic and biodistribution studies. Orally administered ApoE3 polymeric nanoparticles resulted in significantly higher brain donepezil levels after 24 h (84.97 ± 11.54 ng/mg tissue) as compared to pure drug (not detected), suggesting a significant role of surface coating. Together, these findings are promising and offer preclinical evidence for better brain availability of donepezil by oral administration.