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Molecular Imaging |
1 From the Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program (J.K.W., R.P., K.C., O.G., M.R., A.M.L., I.Y.C., X.C., S.S.G.), and Department of Bioengineering (I.Y.C., S.S.G.), Stanford University School of Medicine, the James H. Clark Center, 318 Campus Dr, East Wing, 1st Floor, Stanford, CA 94305-5427. Received January 15, 2007; revision requested May 23; revision received June 9; final version accepted August 1. Supported by the Swiss Foundation of Medical-Biological Grants (J.K.W.); Novartis Research Foundation (J.K.W.); Swiss Society of Radiology (J.K.W.); in part by grants NCI SAIRP (S.S.G.), NHLBI 1 R01 HL078632 (S.S.G.), NCI ICMIC CA114747 P50 (S.S.G.); and the Canary Foundation. Address correspondence to S.S.G. (e-mail: sgambhir{at}stanford.edu).
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 MBC 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.
© RSNA, 2008
Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/2462070536/DC1
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