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Abstract
To improve ultrasound contrast agents targeted to the adhesion molecules P-selectin
and VCAM-1 for the purpose of molecular imaging of atherosclerotic plaques, perfluorocarbon-filled
phospholipid microbubble contrast agents were coupled by a polyethylene glycol-biotin-streptavidin
bridge with mAb MVCAM.A(429), a sialyl Lewis(x) polymer (PAA-sLe(x)), or both (dual).
Approximately three hundred thousand antibody molecules were coupled to the surface
of each microbubble. Recombinant mouse P-selectin and/or VCAM-1 coated on flow chambers
showed saturation of binding at approximately 15 ng/microl, resulting in 800 and 1200
molecules/microm(2) for P-selectin and VCAM-1, respectively. Dual substrates coated
with equal concentrations of P-selectin and VCAM-1 had site densities between 50 and
60% of single substrates. When microbubbles were perfused through flow chambers at
5 x 10(6) microbubbles/ml (wall shear stress from 1.5 to 6 dyn/cm(2)) dual-targeted
microbubbles adhered almost twice as efficiently as single-targeted microbubbles at
6 dyn/cm(2). The present study suggests that dual-targeted contrast agents may be
useful for atherosclerotic plaque detection at physiologically relevant shear stresses.