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DOI: 10.1148/radiol.2483072231
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(Radiology 2008;248:936-944.)
© RSNA, 2008

Molecular Imaging

Dual-targeted Contrast Agent for US Assessment of Tumor Angiogenesis in Vivo1

Jürgen K. Willmann, MD, Amelie M. Lutz, MD, Ramasamy Paulmurugan, PhD, Manishkumar R. Patel, PhD, Pauline Chu, BA, Jarrett Rosenberg, PhD, and Sanjiv S. Gambhir, MD, PhD

1 From the Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program (J.K.W., A.M.L., R.P., M.R.P., J.R., S.S.G.) and Department of Bioengineering (S.S.G.), Stanford University School of Medicine, the James H Clark Center, 318 Campus Dr, East Wing, 1st Floor, Stanford, CA 94305-5427; and Department of Comparative Medicine, Stanford University, Stanford, Calif (P.C.). Received December 31, 2007; revision requested February 15, 2008; revision received February 25; accepted March 6; final version accepted March 17. J.K.W. supported by the Swiss Foundation of Medical-Biological Grants, Novartis Research Foundation, and Swiss Society of Radiology. S.S.G. supported in part by National Cancer Institute Small Animal Imaging Resource Program; National Heart, Lung, and Blood Institute grant 1 R01 HL078632; National Cancer Institute In Vivo Cellular and Molecular Imaging Center grant CA114747 P50; and the Canary Foundation. Address correspondence to S.S.G. (e-mail: sgambhir{at}stanford.edu).

Purpose: To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and {alpha}vβ3 integrin and to compare the US imaging signal obtained from dual-targeted MBs (MBD) with that from single-targeted MBs (MBS) in a murine model of tumor angiogenesis.

Materials and Methods: Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single- and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti–{alpha}vβ3 integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G–labeled control MBs (MBC) and nontargeted nonlabeled MBs (MBN) were tested with VEGFR2-positive and {alpha}vβ3 integrin–positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material–enhanced US by using anti-VEGFR2–targeted MBs (MBV), anti-{alpha}vβ3 integrin–targeted MBs (MBI), MBD, and MBC were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, {alpha}vβ3 integrin, and CD31.

Results: Attachment of MBD to SVR cells (mean, 0.74 MBs per cell ± 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 ± 0.03), and attachment to SVR cells was higher for MBD than for MBV (mean, 0.58 ± 0.09), MBI (mean, 0.42 ± 0.21), MBC (mean, 0.11 ± 0.13), and MBN (mean, 0.01 ± 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MBD (mean, 16.7 ± 7.2) than for MBV (mean, 11.3 ± 5.7), MBI (mean, 7.8 ± 5.3), MBC (mean, 2.8 ± 0.9), and MBN (mean, 1.1 ± 0.4). Immunofluorescence confirmed expression of VEGFR2 and {alpha}vβ3 integrin on tumor vasculature.

Conclusion: Dual-targeted contrast-enhanced US directed at both VEGFR2 and {alpha}vβ3 integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/248/3/936/DC1

© RSNA, 2008