Microparticle adhesive dynamics and rolling mediated by selectin-specific antibodies under flow.
In vitro studies were performed to characterize the relative performance of candidate receptors to target microparticles to inflammatory markers on vascular endothelium. To model the interactions of drug-bearing microparticles or imaging contrast agents with the vasculature, 6 micron polystyrene particles bearing antibodies, peptides, or carbohydrates were perfused over immobilized E- or P-selectin in a flow chamber. Microparticles conjugated with HuEP5C7.g2 (HuEP), a monoclonal antibody (mAb) specific to E- and P-selectin, supported leukocyte-like rolling and transient adhesion at venular shear rates. In contrast, microparticles conjugated with a higher affinity mAb specific for P-selectin (G1) were unable to form bonds at venular flow rates. When both HuEP and G1 were conjugated to the microparticle, HuEP supported binding to P-selectin in flow which allowed G1 to form bonds leading to stable adhesion. While the microparticle attachment and rolling performance was not as stable as that mediated by the natural ligands P-selectin Glycoprotein Ligand-1 or sialyl Lewis(x), HuEP performed significantly better than any previously characterized mAb in terms of mediating microparticle binding under flow conditions. HuEP may be a viable alternative to natural ligands to selectins for targeting particles to inflamed endothelium.
Ham
Anthony Sang Won
AS
Department of Biomedical Engineering, University of Virginia, 415 Lane Road, Charlottesville, Virginia 22908, USA.
Goetz
Douglas J
DJ
Klibanov
Alexander L
AL
Lawrence
Michael B
MB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001783:Blood Flow Velocity / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D019040:E-Selectin / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D036904:Leukocyte Rolling / Q000276:immunology; D008024:Ligands; D051379:Mice; D008863:Microspheres; D018448:Models, Immunological; D019007:P-Selectin / Q000276:immunology; D011137:Polystyrenes / Q000737:chemistry; D033081:Shear Strength
D000911:Antibodies, Monoclonal; D019040:E-Selectin; D008024:Ligands; D019007:P-Selectin; D011137:Polystyrenes