Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to αvβ3

Dilantha B. Ellegala, Howard Leong-Poi, Joan E. Carpenter, Alexander L. Klibanov, Sanjiv Kaul, Mark E. Shaffrey, Jiri Sklenar, Jonathan R. Lindner

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    Abstract

    Background - Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrast-enhanced ultrasound (CEU) with microbubbles targeted to αv-integrins expressed on the neovascular endothelium could be used to image angiogenesis. Methods and Results - Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to αvβ3 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular αv-integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2 ± 1 versus 35 ± 14 mm2, P < 0.001). Tumor blood volume increased by ≈35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, αvβ3-targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from αvβ3-targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7 ± 0.4 versus 3.3 ± 1.0 relative units, P < 0.05). CEU signal from αvβ3-targeted microbubbles was greatest at the periphery of tumors, where αv-integrin expression was most prominent, and correlated well with tumor microvascular blood volume (r = 0.86). Conclusions - CEU with microbubbles targeted to αvβ3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications.

    Original languageEnglish (US)
    Pages (from-to)336-341
    Number of pages6
    JournalCirculation
    Volume108
    Issue number3
    DOIs
    StatePublished - Jul 22 2003

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    Keywords

    • Angiogenesis
    • Cancer
    • Ultrasound

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Cite this

    Ellegala, D. B., Leong-Poi, H., Carpenter, J. E., Klibanov, A. L., Kaul, S., Shaffrey, M. E., Sklenar, J., & Lindner, J. R. (2003). Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to αvβ3. Circulation, 108(3), 336-341. https://doi.org/10.1161/01.CIR.0000080326.15367.0C