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Background: Vulnerable atherosclerotic carotid plaques are prone to rupture resulting in ischemic strokes. Molecular imaging techniques have the potential to assess plaque vulnerability by visualizing molecular markers. Bevacizumab-800CW is a near-infrared fluorescent contrast agent antibody targeting vascular endothelial growth factor-A (VEGF-A). Here, we study if administration of bevacizumab-800CW is safe and can be visualized using multispectral optoacoustic tomography (MSOT) to evaluate atherosclerotic carotid plaques in vivo by visualizing intra-plaque neovascularization.Methods: Healthy volunteers were imaged with MSOT to determine the technical feasibility of human carotid imaging with MSOT. Patients with symptomatic carotid artery stenosis scheduled for carotid artery endarterectomy were intravenously administered with a bolus injection of 4.5 mg bevacizumab-800CW. Before and two days after tracer administration, in vivo non-invasive MSOT was performed. For validation, ex vivo fluorescence molecular imaging of the surgically removed plaque specimen was performed and correlated with histopathology.Results: Administration of 4.5 mg bevacizumab-800CW was safe in five patients. MSOT achieved accurate visualization of the carotid bifurcation area and assessment of the plaque in all five patients. Bevacizumab-800CW-resolved signal could not be detected with MSOT prior to surgery. However, ex vivo analysis of the carotid plaque showed accumulation of bevacizumab-800CW.Conclusions: These first-in-human MSOT and fluorescence molecular imaging results in carotid artery plaques suggest that bevacizumab is a potential tracer for imaging of vulnerable plaques. However, the microdose used here cannot be detected with MSOT. A subsequent phase I dose-finding study is needed to evaluate bevacizumab-800CW in higher doses as a useful optoacoustic imaging agent. Moreover, the development of dedicated optoacoustic contrast agents for signal attenuation of the targeting moiety is advisable for carotid atherosclerotic plaque assessment using MSOT.

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