Abstract
Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewisa individually (MBsLea) or dually with sLea and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MBDual). Assessed by in vitro flow chamber, targeted MB exhibited increased adhesion to platelets as compared to MBControl. While MBsLea rolled slowly on the platelets’ surface, MBDual enhanced the percentage of firm adhesion. In vivo, MB were investigated by ultrasound in a model of ferric chloride induced non-occlusive carotid artery thrombosis. MBsLea and MBDual revealed a higher ultrasound mean acoustic intensity than MBControl (p < 0.05), however MBDual demonstrated no additional increase in mean signal intensity as compared to MBsLea. The degree of carotid artery stenosis on histology correlated well with the ultrasound acoustic intensity of targeted MB (p < 0.05). While dual targeting of MB using fast binding carbohydrate polymers and specific antibodies is a promising strategy to support adhesion to activated platelets under arterial shear stress, these advantages seem not readily translatable to in vivo models.
Highlights
While the degree of stenosis in coronary or cerebral vessels can be quantified by various established clinical imaging techniques, the vulnerability of atherosclerotic plaques and assessing their risk to rupture remain the holy grail in cardiovascular imaging[1,2]
We demonstrated that the microbubble-targeting of P-selectin on platelets using the natural ligand sialyl Lewisa leads to the capture and slow rolling of microbubbles on the endothelial surface, but no firm adhesion[13,14]
Dual targeting using a first ligand with high on-rate such as sialyl Lewis and a second antibody-based ligand with a low off-rate could help improve the success of the target binding of microbubble contrast agents when imaging activated platelets
Summary
While the degree of stenosis in coronary or cerebral vessels can be quantified by various established clinical imaging techniques, the vulnerability of atherosclerotic plaques and assessing their risk to rupture remain the holy grail in cardiovascular imaging[1,2]. This applies in particular to imaging targets under high shear stress conditions, eg in large arterial vessels In this respect, we demonstrated that the microbubble-targeting of P-selectin on platelets using the natural ligand sialyl Lewisa leads to the capture and slow rolling of microbubbles on the endothelial surface, but no firm adhesion[13,14]. We developed and validated a targeted microbubble (MB) with two ligands bound to the microbubble surface: an antibody against LIBS on activated platelets, and the selectin ligand sialyl Lewisa polymer (sLea) This construct was evaluated first in vitro, and thereafter applied to an in vivo ultrasound imaging application simulating a ruptured, non-occlusive plaque of the carotid artery in mice
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