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PPARγ agonist-loaded PLGA -PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies

Silva-Abreu, Marcelle; Calpena, Ana Cristina; Benito, Pol Andres; Romero, Ignacio A.; Roig-Carles, David; Gromnicova, Radka; Espina, Marta; Ferrer, Isidre; Garcia, Maria Luisa and Male, David (2018). PPARγ agonist-loaded PLGA -PEG nanocarriers as a potential treatment for Alzheimer’s disease: in vitro and in vivo studies. International Journal of Nanomedicine, 13 pp. 5577–5590.

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DOI (Digital Object Identifier) Link: https://doi.org/10.2147/IJN.S171490
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Abstract

Objective: The first aim of this study was to develop a nanocarrier that could transport the peroxisome proliferator-activated receptor agonist, pioglitazone (PGZ) across brain endothelium and examine the mechanism of nanoparticle transcytosis. The second aim was to determine whether these nanocarriers could successfully treat a mouse model of Alzheimer’s disease (AD).

Methods: PGZ-loaded nanoparticles (PGZ-NPs) were synthesized by the solvent displacement technique, following a factorial design using poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). The transport of the carriers was assessed in vitro, using a human brain endothelial cell line, cytotoxicity assays, fluorescence-tagged nanocarriers, fluorescence-activated cell sorting, confocal and transmission electron microscopy. The effectiveness of the treatment was assessed in APP/PS1 mice in a behavioral assay and by measuring the cortical deposition of β-amyloid.

Results: Incorporation of PGZ into the carriers promoted a 50x greater uptake into brain endothelium compared with the free drug and the carriers showed a delayed release profile of PGZ in vitro. In the doses used, the nanocarriers were not toxic for the endothelial cells, nor did they alter the permeability of the blood–brain barrier model. Electron microscopy indicated that the nanocarriers were transported from the apical to the basal surface of the endothelium by vesicular transcytosis. An efficacy test carried out in APP/PS1 transgenic mice showed a reduction of memory deficit in mice chronically treated with PGZ-NPs. Deposition of β-amyloid in the cerebral cortex, measured by immunohistochemistry and image analysis, was correspondingly reduced.

Conclusion: PLGA-PEG nanocarriers cross brain endothelium by transcytosis and can be loaded with a pharmaceutical agent to effectively treat a mouse model of AD.

Item Type: Journal Item
Copyright Holders: 2018 The Authors
ISSN: 1178-2013
Project Funding Details:
Funded Project NameProject IDFunding Body
Coordination for the Improvement of Higher Education PersonnelNot Set(CAPES) – Brazil
Not SetMAT2014-59134RSpanish Ministry of Science and Innovation
Nanocarrier transport across the blood-brain barrierNot SetSantander Research Foundation
Not SetBB/K009184/1BBSRC
Keywords: nanoparticle; Alzheimer’s disease; blood–brain barrier; brain endothelium; pioglitazone; APP/PS1 transgenic mouse
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Research Group: Smart Materials
Item ID: 56681
Depositing User: David Male
Date Deposited: 24 Sep 2018 09:40
Last Modified: 23 May 2019 20:04
URI: http://oro.open.ac.uk/id/eprint/56681
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