title: Specific binding, uptake, and transport of ICAM-1-targeted nanocarriers across endothelial and subendothelial cell components of the blood-brain barrier.
abstract: OBJECTIVE
  The blood-brain barrier (BBB) represents a target for therapeutic intervention and an obstacle for brain drug delivery. Targeting endocytic receptors on brain endothelial cells (ECs) helps transport drugs and carriers into and across this barrier. While most receptors tested are associated with clathrin-mediated pathways, clathrin-independent routes are rather unexplored. We have examined the potential for one of these pathways, cell adhesion molecule (CAM)-mediated endocytosis induced by targeting intercellular adhesion molecule -1 (ICAM-1), to transport drug carriers into and across BBB models.
  
  
  METHODS
  Model polymer nanocarriers (NCs) coated with control IgG or antibodies against ICAM-1 (IgG NCs vs. anti-ICAM NCs; ~250-nm) were incubated with human brain ECs, astrocytes (ACs), or pericytes (PCs) grown as monocultures or bilayered (endothelial+subendothelial) co-cultures.
  
  
  RESULTS
  ICAM-1 was present and overexpressed in disease-like conditions on ECs and, at a lesser extent, on ACs and PCs which are BBB subendothelial components. Specific targeting and CAM-mediated uptake of anti-ICAM NCs occurred in these cells, although this was greater for ECs. Anti-ICAM NCs were transported across endothelial monolayers and endothelial+subendothelial co-cultures modeling the BBB.
  
  
  CONCLUSIONS
  CAM-mediated transport induced by ICAM-1 targeting operates in endothelial and subendothelial cellular components of the BBB, which may provide an avenue to overcome this barrier.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland College Park, Maryland, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Hsu
authors.forename: Jeff
authors.initials: J
authors.lastname: Rappaport
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
mesh_terms: D000906:Antibodies / Q000276:immunology; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D004337:Drug Carriers; D018799:Intercellular Adhesion Molecule-1