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Ultrasound Med Biol. 2018 Jun;44(6):1155-1163. doi: 10.1016/j.ultrasmedbio.2018.01.001. Epub 2018 Mar 13.

Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress.

Author information

1
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA.
2
Department of Surgery, University of Arizona, Tucson, Arizona, USA.
3
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA; Portland Veterans Affairs Medical Center, Portland, Oregon, USA.
4
NuvOx LLC, Tucson, Arizona, USA.
5
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA; Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon, USA. Electronic address: linderj@ohsu.edu.

Abstract

The aim of this study was to evaluate a panel of endothelium-targeted microbubble (MB) ultrasound contrast agents bearing small peptide ligands as a human-ready approach for molecular imaging of markers of high-risk atherosclerotic plaque. Small peptide ligands with established affinity for human P-selectin, VCAM-1, LOX-1 and von Willebrand factor (VWF) were conjugated to the surface of lipid-stabilized MBs. Contrast-enhanced ultrasound (CEUS) molecular imaging of the thoracic aorta was performed in wild-type and gene-targeted mice with advanced atherosclerosis (DKO). Histology was performed on carotid endarterectomy samples from patients undergoing surgery for unstable atherosclerosis to assess target expression in humans. In DKO mice, CEUS signal for all four targeted MBs was significantly higher than that for control MBs, and was three to sevenfold higher than in wild-type mice, with the highest signal achieved for VCAM-1 and VWF. All molecular targets were present on the patient plaque surface but expression was greatest for VCAM-1 and VWF. We conclude that ultrasound contrast agents bearing small peptide ligands feasible for human use can be targeted against endothelial cell adhesion molecules for inflammatory cells and platelets for imaging advanced atherosclerotic disease.

KEYWORDS:

Atherosclerosis; Contrast-enhanced ultrasound; Microbubbles; Molecular Imaging

[Indexed for MEDLINE]

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