Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents
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ncomms15623.pdf
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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.
Date Issued
June 2017
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
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1038/NCOMMS15623
