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.

DOI: https://doi.org/10.2147/IJN.S171490

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.

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About

• Item ORO ID
• 56681
• Item Type
• Journal Item
• ISSN
• 1178-2013
• Project Funding Details

• Funded Project Name	Project ID	Funding Body
  Coordination for the Improvement of Higher Education Personnel	Not Set	(CAPES) – Brazil
  Not Set	MAT2014-59134R	Spanish Ministry of Science and Innovation
  Nanocarrier transport across the blood-brain barrier	Not Set	Santander Research Foundation
  Not Set	BB/K009184/1	BBSRC

• Keywords
• nanoparticle; Alzheimer’s disease; blood–brain barrier; brain endothelium; pioglitazone; APP/PS1 transgenic mouse
• Academic Unit or 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
• Copyright Holders
• © 2018 The Authors
• Depositing User
• David Male