title: Donepezil loaded PLGA-b-PEG nanoparticles: their ability to induce destabilization of amyloid fibrils and to cross blood brain barrier in vitro.
abstract: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. Cholinesterase inhibitors (ChEIs) are commonly used for symptomatic treatment of neural transmission improvement in AD. Donepezil is a reversible and non-competitive ChEI which is clinically used for palliative treatment of AD. The aim of the present study was to investigate the destabilizing effect of donepezil loaded poly(lactic-co-glycolic acid)-block-poly (ethylene glycol) [PLGA-b-PEG] nanoparticles on fibril formation in vitro and the ability of these nanoparticles to cross blood brain barrier (BBB) using in vitro BBB model and the neuroprotective effects of free donepezil and donepezil loaded PLGA-b-PEG nanoparticles. Donepezil loaded PLGA-b-PEG nanoparticles were prepared with double emulsion method. Destabilizing effect of these donepezil loaded particles on the amyloid-beta fibril (Aβ1-40and Aβ1-42) formation was determined in vitro. Nanoparticles were found to have small particle size and have destabilizing effect on fibril formation. In vitro BBB model was successfully prepared. Nanoparticles showed the ability to cross the BBB and showed a controlled release profile in this system. IL-1β, IL-6, GM-CSF, TGF-β, MCP-1 and TNF-α levels were found to be increased in both gene and protein expression levels in astrocytes incubated with amyloid fibrils in in vitro BBB model suggesting an increased inflammation. Free donepezil and donepezil loaded nanoparticle administration caused a significant dose-dependent decrease in both gene and protein expression levels of IL-1β, IL-6, GM-CSF and TNF-α. No significant changes were observed for TGF-β and MCP-1.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
authors.forename: Ipek
authors.initials: I
authors.lastname: Baysal
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
authors.forename: Gulberk
authors.initials: G
authors.lastname: Ucar
authors.affiliation: Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
authors.forename: Merve
authors.initials: M
authors.lastname: Gultekinoglu
authors.affiliation: Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey.
authors.forename: Kezban
authors.initials: K
authors.lastname: Ulubayram
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey. samiye@hacettepe.edu.tr.
authors.forename: Samiye
authors.initials: S
authors.lastname: Yabanoglu-Ciftci
mesh_terms: D000682:Amyloid / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053758:Nanoparticles / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols; D011098:Polyglactin 910; D055550:Protein Stability / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004337:Drug Carriers; D007189:Indans; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010880:Piperidines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D000077265:Donepezil; D012293:Rifampin
keywords: Alzheimer’s disease; Donepezil; In vitro; Nanoparticle; PLGA-b-PEG