From the Division of Cardiology, Department of Medicine (F.S.V., M.L.P.);
Division of Cardiothoracic Surgery, Department of Surgery (R.J.J., W.R.W.);
and Department of Cell Biology and Physiology and Center for Biologic Imaging
(S.C.W., S.M.A.), University of Pittsburgh, Pittsburgh, Pa; and Mallinckrodt
Medical, Inc, St Louis, Mo (S.K., G.H.B.).
Correspondence to Flordeliza S. Villanueva, MD, University of Pittsburgh, 200 Lothrop St, S568 Scaife Hall, Pittsburgh, PA 15213. E-mail villanuevafs{at}msx.upmc.edu
Background—Preclinical
atherosclerosis is associated with increased
endothelial cell (EC) expression of leukocyte adhesion
molecules (LAMs), which mediate monocyte adhesion during atherogenesis.
Identification of cell-surface LAMs may uniquely allow assessment of
endothelial function, but there are no in vivo methods
for detecting LAMs. We tested a new microbubble designed to bind to and
allow specific ultrasound detection of intercellular adhesion
molecule-1 (ICAM-1).
Methods and Results—A perfluorobutane gas–filled lipid-derived
microsphere with monoclonal antibody to ICAM-1 covalently bound
to the bubble shell was synthesized. Bubbles with either nonspecific
IgG or no protein on the shell were synthesized as controls. Coverslips
of cultured human coronary artery ECs were placed in a
parallel-plate perfusion chamber and exposed to 1 of the 3 microbubble
species, followed by perfusion with culture medium. Experiments were
performed with either normal or interleukin-1ß–activated ECs
overexpressing ICAM-1, and bubble adherence was quantified with
epifluorescent videomicroscopy. There was limited adherence of
control bubbles to normal or activated ECs, whereas a 40-fold
increase in adhesion occurred when anti–ICAM-1–conjugated bubbles
were exposed to activated ECs compared with normal ECs
(8.1±3.5 versus 0.21±0.09 bubbles per cell, respectively,
P<0.001). Although diminished, this difference
persisted even after perfusion at higher wall shear rates.
Conclusions—A gas-filled microbubble with anti–ICAM-1 antibody
on its shell specifically binds to activated ECs overexpressing
ICAM-1. Diagnostic ultrasound in conjunction with targeted
contrast agents has the unique potential to characterize cell
phenotype in vivo.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Microbubbles Targeted to Intercellular Adhesion Molecule-1 Bind to Activated Coronary Artery Endothelial Cells
Key Words: cells • microspheres • cell adhesion molecules • endothelium
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