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Alzheimers Res Ther. 2013 Nov 27;5(6):51. doi: 10.1186/alzrt225. eCollection 2013.

Nanoparticulate flurbiprofen reduces amyloid-β42 generation in an in vitro blood-brain barrier model.

Author information

1
Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
2
Institute of Pharmaceutical Technology and Biopharmacy, University of Muenster, Muenster, Germany.
3
Department of Cell Biology and Applied Virology, Fraunhofer Institute for Biomedical Engineering, St. Ingbert, Germany.
4
Molecular and Cellular Oncology/Mainz Screening Center (MSC), ENT-Department, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
5
Department of Neuropathology, Heinrich Heine University, Duesseldorf, Germany.
6
The Biophysical Interdisciplinary Schottenstein Center for the Research and Technology of the Cellome, Bar Ilan University, Ramat gan, Israel.
7
Department of Neurology, Medical University of Graz, Graz, Austria.
8
NeuroScios GmbH, St. Radegund/Graz, Austria.

Abstract

INTRODUCTION:

The amyloid-β42 (Aβ42) peptide plays a crucial role in the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disorder affecting the elderly. Over the past years, several approaches and compounds developed for the treatment of AD have failed in clinical studies, likely in part due to their low penetration of the blood-brain barrier (BBB). Since nanotechnology-based strategies offer new possibilities for the delivery of drugs to the brain, this technique is studied intensively for the treatment of AD and other neurological disorders.

METHODS:

The Aβ42 lowering drug flurbiprofen was embedded in polylactide (PLA) nanoparticles by emulsification-diffusion technique and their potential as drug carriers in an in vitro BBB model was examined. First, the cytotoxic potential of the PLA-flurbiprofen nanoparticles on endothelial cells and the cellular binding and uptake by endothelial cells was studied. Furthermore, the biological activity of the nanoparticulate flurbiprofen on γ-secretase modulation as well as its in vitro release was examined. Furthermore, the protein corona of the nanoparticles was studied as well as their ability to transport flurbiprofen across an in vitro BBB model.

RESULTS:

PLA-flurbiprofen nanoparticles were endocytosed by endothelial cells and neither affected the vitality nor barrier function of the endothelial cell monolayer. The exposure of the PLA-flurbiprofen nanoparticles to human plasma occurred in a rapid protein corona formation, resulting in their decoration with bioactive proteins, including apolipoprotein E. Furthermore, luminally administered PLA-flurbiprofen nanoparticles in contrast to free flurbiprofen were able to modulate γ-secretase activity by selectively decreasing Aβ42 levels in the abluminal compartment of the BBB model.

CONCLUSIONS:

In this study, we were able to show that flurbiprofen can be transported by PLA nanoparticles across an in vitro BBB model and most importantly, the transported flurbiprofen modulated γ-secretase activity by selectively decreasing Aβ42 levels. These results demonstrate that the modification of drugs via embedding in nanoparticles is a promising tool to facilitate drug delivery to the brain, which enables future development for the treatment of neurodegenerative disorders like AD.

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