BioCentury
ARTICLE | Distillery Techniques

Disease models

August 16, 2017 6:00 PM UTC

Self-assembling multicellular BBB spheroids could help screen compounds for BBB permeability. The spheroids self-assembled from co-cultures of primary human astrocytes, brain vascular pericytes and either brain microvascular endothelial cells or a human cerebral microvascular endothelial cell line, and consisted of an astrocyte core encased in an outer layer of brain endothelial cells and pericytes. The outer layer of the spheroids exhibited BBB features, including high expression of tight junction proteins claudin 5 (CLDN5) and occludin (OCLN), VEGF-dependent permeability and high expression of the ATP-binding cassette sub-family B member 1 (ABCB1; MDR1; PGP; CD243) efflux pump. Spheroids incubated with the BBB-permeable compound buparlisib accumulated the compound, whereas spheroids incubated with the non-BBB-permeable drug Tafinlar dabrafenib did not accumulate the drug. Also in the spheroids, screening of 16 fluorescently labeled peptides identified four that had high levels of permeability, and IV injection into mice showed all four peptides accumulated in brain parenchyma. Next steps include using the spheroids to test the BBB permeability of additional compounds.

Novartis AG has buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, in Phase I through Phase III testing for various cancers...