title: Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1.
abstract: Targeting nanocarriers (NC) to endothelial cell adhesion molecules including Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1 or CD31) improves drug delivery and pharmacotherapy of inflammation, oxidative stress, thrombosis and ischemia in animal models. Recent studies unveiled that hydrodynamic conditions modulate endothelial endocytosis of NC targeted to PECAM-1, but the specificity and mechanism of effects of flow remain unknown. Here we studied the effect of flow on endocytosis by human endothelial cells of NC targeted by monoclonal antibodies Ab62 and Ab37 to distinct epitopes on the distal extracellular domain of PECAM. Flow in the range of 1-8dyn/cm(2), typical for venous vasculature, stimulated the uptake of spherical Ab/NC (~180nm diameter) carrying ~50 vs 200 Ab62 and Ab37 per NC, respectively. Effect of flow was inhibited by disruption of cholesterol-rich plasmalemma domains and deletion of PECAM-1 cytosolic tail. Flow stimulated endocytosis of Ab62/NC and Ab37/NC via eliciting distinct signaling pathways mediated by RhoA/ROCK and Src Family Kinases, respectively. Therefore, flow stimulates endothelial endocytosis of Ab/NC in a PECAM-1 epitope specific manner. Using ligands of binding to distinct epitopes on the same target molecule may enable fine-tuning of intracellular delivery based on the hemodynamic conditions in the vascular area of interest.
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA19104, USA; Vascular Biology Section, Department of Medicine, Boston University, Boston, MA 02421, USA.
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA19104, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.affiliation: Department of Pathology & Lab Medicine and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA19104, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Davies
authors.affiliation: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Eckmann
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
authors.affiliation: Department of Pharmacology and Center for Translational Targeted Therapeutics and Nanomedicine of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA19104, USA. Electronic address: muzykantov@mail.med.upenn.edu.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D004705:Endocytosis; D000939:Epitopes / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D011137:Polystyrenes / Q000008:administration & dosage / Q000737:chemistry; D012212:Rheology; D013314:Stress, Mechanical
chemical_list: D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D000939:Epitopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011137:Polystyrenes
keywords: Cell adhesion molecules; Endocytosis; Endothelial cells; Fluid shear stress; Intracellular delivery; Vascular immunotargeting