Publications

Targeting therapeutic nanocarriers (NCs) to endothelial receptors favours transport across the blood-brain barrier (BBB), a main obstacle to access the brain. While these strategies compel validation in animals, quantitative sub-cellular resolution is non-viable in vivo. BBB-on-chip (BBB-oC) devices can help. Illustrating this, we used a BBB-oC comprising a lateral channel containing a human brain endothelial lining and a central chamber containing hydrogel-embedded pericytes and astrocytes. We studied NCs targeting intercellular adhesion molecule-1 (ICAM-1), a cell-surface protein overexpressed in pathology and involved in CAM-mediated transport. Brain access was validated in vivo after injection of NCs coated with anti-ICAM-1 vs. control IgG. ICAM-1 expression was verified in vitro using endothelial cells, pericytes, and astrocytes (756-, 511-, 690-fold over non-specific signal under TNF alpha). VE-cadherin presence and lack of dextran leakage demonstrated a restrictive BBB-oC barrier. Data showed endothelial targeting of anti-ICAM-1 NCs (428 NCs/cell at 1 h), uptake (60% of cell-interacting NCs), and transcytosis (90%; 24 h) downregulated by a CAM-pathway inhibitor (88% decay; 1 h). Non-transcyosed NCs trafficked to lysosomes, while transcytosed NCs interacted with pericytes and astrocytes (2643 NCs/cell; 24 h) and entered them (90% of transcytosed NCs). This BBB-oC represents a valuable model to evaluate ICAM-1-mediated transcytosis, complementing animal studies.

JTD Keywords: Blood-brain barrier, Design, Drug-delivery, Endothelial and basolateral interactions, Endothelium, Icam-1 targeting, Icam-1-targeted nanocarriers, Nanoparticles, Organ-on-a-chip, Targeted nanocarriers, Transcytosis mechanism, Transport