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

Federico Moccetti, Craig C. Weinkauf, Brian P. Davidson, J. Todd Belcik, Edmund R. Marinelli, Evan Unger, Jonathan Lindner

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    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.

    Original languageEnglish (US)
    JournalUltrasound in Medicine and Biology
    DOIs
    StateAccepted/In press - Jan 1 2018

    Fingerprint

    arteriosclerosis
    Molecular Imaging
    Vascular Cell Adhesion Molecule-1
    von Willebrand Factor
    markers
    peptides
    Ultrasonography
    Atherosclerosis
    Oxidative Stress
    Ligands
    Inflammation
    mice
    Contrast Media
    Peptides
    ligands
    Microbubbles
    Carotid Endarterectomy
    Cell Adhesion Molecules
    Atherosclerotic Plaques
    endothelium

    Keywords

    • Atherosclerosis
    • Contrast-enhanced ultrasound
    • Microbubbles
    • Molecular Imaging

    ASJC Scopus subject areas

    • Radiological and Ultrasound Technology
    • Biophysics
    • Acoustics and Ultrasonics

    Cite this

    Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress. / Moccetti, Federico; Weinkauf, Craig C.; Davidson, Brian P.; Belcik, J. Todd; Marinelli, Edmund R.; Unger, Evan; Lindner, Jonathan.

    In: Ultrasound in Medicine and Biology, 01.01.2018.

    Research output: Contribution to journalArticle

    @article{fa006139268c4305ad3732f2ca5b3e58,
    title = "Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress",
    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",
    author = "Federico Moccetti and Weinkauf, {Craig C.} and Davidson, {Brian P.} and Belcik, {J. Todd} and Marinelli, {Edmund R.} and Evan Unger and Jonathan Lindner",
    year = "2018",
    month = "1",
    day = "1",
    doi = "10.1016/j.ultrasmedbio.2018.01.001",
    language = "English (US)",
    journal = "Ultrasound in Medicine and Biology",
    issn = "0301-5629",
    publisher = "Elsevier USA",

    }

    TY - JOUR

    T1 - Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress

    AU - Moccetti, Federico

    AU - Weinkauf, Craig C.

    AU - Davidson, Brian P.

    AU - Belcik, J. Todd

    AU - Marinelli, Edmund R.

    AU - Unger, Evan

    AU - Lindner, Jonathan

    PY - 2018/1/1

    Y1 - 2018/1/1

    N2 - 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.

    AB - 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.

    KW - Atherosclerosis

    KW - Contrast-enhanced ultrasound

    KW - Microbubbles

    KW - Molecular Imaging

    UR - http://www.scopus.com/inward/record.url?scp=85043478430&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85043478430&partnerID=8YFLogxK

    U2 - 10.1016/j.ultrasmedbio.2018.01.001

    DO - 10.1016/j.ultrasmedbio.2018.01.001

    M3 - Article

    C2 - 29548756

    AN - SCOPUS:85043478430

    JO - Ultrasound in Medicine and Biology

    JF - Ultrasound in Medicine and Biology

    SN - 0301-5629

    ER -