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

Choi-Fong Cho (), Justin M. Wolfe, Colin M. Fadzen, David Calligaris, Kalvis Hornburg, E. Antonio Chiocca, Nathalie Y. R. Agar, Bradley L. Pentelute and Sean E. Lawler ()
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Choi-Fong Cho: Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School
Justin M. Wolfe: Massachusetts Institute of Technology
Colin M. Fadzen: Massachusetts Institute of Technology
David Calligaris: Brigham and Women’s Hospital, Harvard Medical School
Kalvis Hornburg: Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School
E. Antonio Chiocca: Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School
Nathalie Y. R. Agar: Brigham and Women’s Hospital, Harvard Medical School
Bradley L. Pentelute: Massachusetts Institute of Technology
Sean E. Lawler: Harvey Cushing Neuro-Oncology Laboratories, Brigham and Women’s Hospital, Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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: 2017
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DOI: 10.1038/ncomms15623

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