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

Abstract

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 diblock copolymer methoxy poly­(ethylene glycol)–polycaprolactone (mPEG–PCL) have been used to boost the delivery of donepezil to the brain. mPEG–PCL is an amphiphilic diblock 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 were performed by using a nanoprecipitation method and 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 a sustained drug release pattern. Cellular uptake studies confirmed 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 the 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.

Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects

“…Lipid NPs of zidovudine and saquinavir intended for the CNS showed promising results in cell cultures in vitro (Kuo and Wang, 2014;Joshy et al, 2016), and SLN-based formulations of efavirez (Gupta et al, 2017) and nevirapine (Lahkar and Kumar Das, 2018) exhibited an improved central in vivo bioavailability (BA). In the case of efavirenz, the strategy was to circumvent the BBB by means of the nasal administration of the nanoparticles, while in the nevirapine case the administration was by intravenous (IV) route and the improved biodistribution was attributed to the coating (polysorbate 80), able to enrich the protein crown in ApoE, resulting in a higher passage through the BBB due to the contribution of receptor-mediated transcytosis (Li et al, 2018;Krishna et al, 2019).…”

Preclinical pharmacokinetics of trigonelline using ultra‐performance liquid chromatography–tandem mass spectrometry and pharmacological studies targeting type 2 diabetes

“…The plasma concentrations‐time profile of Tr was plotted to generate pharmacokinetic parameters. Pharmacokinetic parameters were assessed using Phoenix WinNolin8.0 (Certera™, USA) with compartmental and non‐compartmental modeling [22,23].…”

Nanoparticles: A Hope for the Treatment of Inflammation in CNS

“…For example, l -DOPA-AuNF improved the penetration of l -DOPA across the BBB ( Gonzalez-Carter et al, 2019 ). ApoE3 polymeric nanoparticles loaded with donepezil showed an enhanced brain uptake of the drug, binding to amyloid beta with high affinity and accelerating its clearance ( Krishna et al, 2019 ). Therefore, it is important to further develop the NPs with high BBB penetration capacity to encapsulate drugs with potent anti-inflammatory and anti-apoptosis effects such as galantamine, noferriamine, rivarasmine, risperidone, curcumin, quercetin, and ropinirole ( Cao et al, 2016 ; Agrawal et al, 2018 ; Dudhipala and Gorre, 2020 ) for the treatment of AD and PD in the future.…”