Flurbiprofen-loaded Nanoparticles Can Cross a Primary Porcine In vitro Blood-brain Barrier Model to Reduce Amyloid-ÃÂ²42 BurdenJulia Stab1,2, Iavor Zlatev3, Bastian Raudszus3, Sabrina Meister4, Claus U Pietrzik4, Klaus Langer3, Hagen von Briesen1 and Sylvia Wagner1*
- *Corresponding Author:
- Sylvia Wagner
Department Bioprocessing & Bioanalytics
Fraunhofer Institute for Biomedical Engineering
Tel: +49 (0) 6897/9071-291
Fax: +49 (0) 6897/9071-490
E-mail: [email protected]
Received date: April 07, 2016; Accessed date: April 22, 2016; Published date: April 30, 2016
Citation: Stab J, Zlatev I, Raudszus B, Meister S, Pietrzik CU, et al. (2016) Flurbiprofen-loaded Nanoparticles Can Cross a Primary Porcine In vitro Blood-brain Barrier Model to Reduce Amyloid-ß42 Burden. J Nanomedine Biotherapeutic Discov 6:140. doi:10.4172/2155-983X.1000140
Copyright: © 2016 Stab J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Elevated amyloid-β42 (Aβ42) in the brain is expected to cause
(AD). Reducing Aβ42 is therefore a cornerstone in causal drug development. Nevertheless, many promising substances failed in clinical trials, because reaching the target organ in vivo is difficult. The brain is protected by the Blood-Brain Barrier (BBB) that shields off most molecules to maintain the brain homeostasis. Brain-targeted nanoparticles are one successful tool to bypass this problem: by acting as Trojan horses they carry embedded drugs across the BBB for brain disorder treatment. Here, flurbiprofen, a γ-secretase modulator, was embedded in Poly(Lactic Acid) (PLA) nanoparticles. We tested if the drug-loaded nanoparticles affected the integrity of our advanced in vitro BBB model in transendothelial electrical resistance measurements and permeability assays, and investigated the nanoparticle-cell interaction in flow cytometry and confocal laser scanning microscopy. Furthermore, we assessed the drug transport capacity by highperformance liquid
and the biological efficacy of the embedded drug in an Aβ42-detecing ELISA. We also verified the viability of the AD model cells by a cellular viability assay. After adding flurbiprofen-loaded nanoparticles to the blood compartment of a Transwell® model, the drug was detectable in the brain compartment, where it induced an Aβ42 lowering effect. Flurbiprofen from nanoparticles crossed the BBB without impairing barrier integrity, whereas the free drug was highly cytotoxic and destroyed the barrier. Ligand coupling of
E3 to the nanoparticles increased cellular uptake. Hence, we expect an even more pronounced Aβ42 reducing effect for apolipoprotein-modified, flurbiprofen-loaded nanoparticles. In conclusion, we enabled transport of a hardly permeable drug across an advanced in vitro BBB model, opening opportunities in the treatment and prevention of AD and other brain disorders. Using a primary porcine BBB model that displays excellent barrier characteristics, we show that flurbiprofen-loaded nanoparticles reduce Aβ42 burden without impairing barrier function.