US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice

Jürgen K. Willmann, Ramasamy Paulmurugan, Kai Chen, Olivier Gheysens, Martin Rodriguez-Porcel, Amelie M. Lutz, Ian Y. Chen, Xiaoyuan Chen, Sanjiv S. Gambhir

Research output: Contribution to journalArticle

257 Scopus citations

Abstract

Purpose: To prospectively evaluate contrast material-enhanced ultrasonography (US) with microbubbles targeted to vascular endothelial growth factor receptor type 2 (VEGFR2) for imaging tumor angiogenesis in two murine tumor models. Materials and Methods: Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. A US contrast agent, consisting of encapsulated gaseous microbubbles, was developed specifically to bind to VEGFR2 (by using anti-VEGFR2 antibodies and biotin-streptavidin interaction) which is up-regulated on endothelial cells of tumor blood vessels. VEGFR2-targeted microbubbles (MBV), control microbubbles (MBC), and nonlabeled microbubbles (MBN) were tested for binding specificity on cells expressing VEGFR2 (mouse angiosarcoma SVR cells) and control cells (mouse skeletal myoblast C2C12 cells). Expression of mouse VEGFR2 in culture cells was tested with immunocytochemical and Western blot analysis. Contrast-enhanced US imaging with MBV and MB C was performed in 28 tumor-bearing nude mice (mouse angiosarcoma, n = 18; rat malignant glioma, n = 10). Differences were calculated by using analysis of variance. Results: In cell culture, adherence of MBV on SVR cells (2.1 microbubbles per SVR cell) was significantly higher than adherence of control microbubbles (0.01-0.10 microbubble per SVR cell; P < .001) and significantly more MBV attached to SVR cells than to C2C12 cells (0.15 microbubble per C2C12 cell; P < .001). In vivo, contrast-enhanced US imaging showed significantly higher average video intensity when using MBV compared with MBC for angiosarcoma and malignant glioma tumors (P < .001). Results of immunohistochemical analysis confirmed VEGFR2 expression on vascular endothelial cells of both tumor types. Conclusion: US imaging with contrast microbubbles targeted to VEGFR2 allows noninvasive visualization of VEGFR2 expression in tumor vessels in mice.

Original languageEnglish (US)
Pages (from-to)508-518
Number of pages11
JournalRadiology
Volume246
Issue number2
DOIs
StatePublished - Feb 2008

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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    Willmann, J. K., Paulmurugan, R., Chen, K., Gheysens, O., Rodriguez-Porcel, M., Lutz, A. M., Chen, I. Y., Chen, X., & Gambhir, S. S. (2008). US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice. Radiology, 246(2), 508-518. https://doi.org/10.1148/radiol.2462070536