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Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents

Author(s)
Calligaris, David; Hornburg, Kalvis; Chiocca, E. Antonio; Agar, Nathalie Y. R.; Lawler, Sean E.; Cho, Choi-Fong; Wolfe, Justin; Fadzen, Colin M.; Pentelute, Bradley L.; ... Show more Show less
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Abstract
Culture-based blood-brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-Assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robust in vitro BBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics.
Date issued
2017-06
URI
http://hdl.handle.net/1721.1/113429
Department
Massachusetts Institute of Technology. Department of Chemistry
Journal
Nature Communications
Publisher
Nature Publishing Group
Citation
Cho, Choi-Fong et al. “Blood-Brain-Barrier Spheroids as an in Vitro Screening Platform for Brain-Penetrating Agents.” Nature Communications 8 (June 2017): 15623 © 2017 The Author(s)
Version: Final published version
ISSN
2041-1723

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