PUBLICATION
Donepezil-Loaded Nanocarriers for the Treatment of Alzheimer's Disease: Superior Efficacy of Extracellular Vesicles Over Polymeric Nanoparticles
- Authors
- Oliveira Silva, R., Counil, H., Rabanel, J.M., Haddad, M., Zaouter, C., Ben Khedher, M.R., Patten, S.A., Ramassamy, C.
- ID
- ZDB-PUB-240206-11
- Date
- 2024
- Source
- International Journal of Nanomedicine 19: 107710961077-1096 (Journal)
- Registered Authors
- Keywords
- Alzheimer’s disease, PLA-PEG, bEnd.3 cells, donepezil, extracellular vesicular, zebrafish
- MeSH Terms
-
- Zebrafish
- Polymers
- Drug Carriers
- Nanoparticles*
- Endothelial Cells
- Polyesters
- Acetylcholinesterase
- Cholinesterase Inhibitors/pharmacology
- Animals
- Donepezil
- Humans
- Extracellular Vesicles*
- Polyethylene Glycols
- Tissue Distribution
- Alzheimer Disease*/drug therapy
- PubMed
- 38317848 Full text @ Int. J. Nanomedicine
Citation
Oliveira Silva, R., Counil, H., Rabanel, J.M., Haddad, M., Zaouter, C., Ben Khedher, M.R., Patten, S.A., Ramassamy, C. (2024) Donepezil-Loaded Nanocarriers for the Treatment of Alzheimer's Disease: Superior Efficacy of Extracellular Vesicles Over Polymeric Nanoparticles. International Journal of Nanomedicine. 19:107710961077-1096.
Abstract
Introduction Drug delivery across the blood-brain barrier (BBB) is challenging and therefore severely restricts neurodegenerative diseases therapy such as Alzheimer's disease (AD). Donepezil (DNZ) is an acetylcholinesterase (AChE) inhibitor largely prescribed to AD patients, but its use is limited due to peripheral adverse events. Nanodelivery strategies with the polymer Poly (lactic acid)-poly(ethylene glycol)-based nanoparticles (NPs-PLA-PEG) and the extracellular vesicles (EVs) were developed with the aim to improve the ability of DNZ to cross the BBB, its brain targeting and efficacy.
Methods EVs were isolated from human plasma and PLA-PEG NPs were synthesized by nanoprecipitation. The toxicity, brain targeting capacity and cholinergic activities of the formulations were evaluated both in vitro and in vivo.
Results EVs and NPs-PLA-PEG were designed to be similar in size and charge, efficiently encapsulated DNZ and allowed sustained drug release. In vitro study showed that both formulations EVs-DNZ and NPs-PLA-PEG-DNZ were highly internalized by the endothelial cells bEnd.3. These cells cultured on the Transwell® model were used to analyze the transcytosis of both formulations after validation of the presence of tight junctions, the transendothelial electrical resistance (TEER) values and the permeability of the Dextran-FITC. In vivo study showed that both formulations were not toxic to zebrafish larvae (Danio rerio). However, hyperactivity was evidenced in the NPs-PLA-PEG-DNZ and free DNZ groups but not the EVs-DNZ formulations. Biodistribution analysis in zebrafish larvae showed that EVs were present in the brain parenchyma, while NPs-PLA-PEG remained mainly in the bloodstream.
Conclusion The EVs-DNZ formulation was more efficient to inhibit the AChE enzyme activity in the zebrafish larvae head. Thus, the bioinspired delivery system (EVs) is a promising alternative strategy for brain-targeted delivery by substantially improving the activity of DNZ for the treatment of AD.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping