title: Modulating targeted adhesion of an ultrasound contrast agent to dysfunctional endothelium.
abstract: The early stages of atherosclerosis are characterized by increased endothelial cell (EC) surface expression of leukocyte adhesion molecules (LAMs). Ultrasound detection of acoustically active LAM-targeted microbubbles might provide a means to noninvasively assess the functional status of the endothelium. Toward this end, a lipid-based perfluorobutane-filled microbubble was synthesized with various densities of anti-ICAM-1 monoclonal antibodies conjugated to the bubble shell. We hypothesized that modulating the surface antibody density would permit regulation of the adhesion characteristics of the microbubbles, and that microbubble adhesion would be dependent on local wall shear rate. Coverslips of cultured human coronary artery ECs were exposed to microbubbles with various surface antibody densities (1%, 5%, 10%, 50%, 75%, and 100% of maximum coverage) at various wall shear rates (100, 175, 250, 350, and 500 s-1) in a parallel plate perfusion chamber. ECs were either normal or activated by interleukin-1 beta to overexpress ICAM-1. Adhesion was greater to activated vs. normal ECs (p < 0.001), increased with increasing surface antibody density (p < 0.01), and decreased with increasing wall shear rate (p = 0.02). We conclude that shell antibody density and wall shear rate are critical parameters controlling differential microbubble adhesion. This phenomenon might ultimately permit imaging of clinically relevant LAM expression in vivo.
authors.affiliation: Department of Bioengineering, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Gregory E R
authors.initials: GE
authors.lastname: Weller
authors.forename: Flordeliza S
authors.initials: FS
authors.lastname: Villanueva
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.forename: William R
authors.initials: WR
authors.lastname: Wagner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000145:classification / Q000494:pharmacology; D000937:Antigen-Antibody Reactions / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003287:Contrast Media / Q000378:metabolism*; D003331:Coronary Vessels / Q000166:cytology / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D005466:Fluorocarbons; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008863:Microspheres; D011485:Protein Binding; D012016:Reference Values; D012680:Sensitivity and Specificity; D033081:Shear Strength; D013314:Stress, Mechanical; D013499:Surface Properties; D014463:Ultrasonography; D014657:Vasculitis / Q000000981:diagnostic imaging*
chemical_list: D000911:Antibodies, Monoclonal; D003287:Contrast Media; D005466:Fluorocarbons; D018799:Intercellular Adhesion Molecule-1; C108042:perfluorobutane