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In Vivo VEGF Imaging with Radiolabeled Bevacizumab in a Human Ovarian Tumor Xenograft

¹ Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; ² Department of Nuclear Medicine and Molecular Imaging, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; ³ Department of Pathology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; ⁴ Department of Nuclear Medicine and PET Research, VU Medical Center, Amsterdam, The Netherlands; and ⁵ Department of Hospital and Clinical Pharmacy, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands

Correspondence: For correspondence or reprints contact: Elisabeth G. de Vries, MD, PhD, Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: e.g.e.de.vries{at}int.umcg.nl

Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGF-induced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for noninvasive in vivo VEGF visualization and quantification with the single -emitting isotope ¹¹¹In and the PET isotope ⁸⁹Zr. Methods: Labeling, stability, and binding studies were performed. Nude mice with a human SKOV-3 ovarian tumor xenograft were injected with ⁸⁹Zr-bevacizumab, ¹¹¹In-bevacizumab, or human ⁸⁹Zr-IgG. Human ⁸⁹Zr-IgG served as an aspecific control antibody. Small-animal PET and microCT studies were obtained at 24, 72, and 168 h after injection of ⁸⁹Zr-bevacizumab and ⁸⁹Zr-IgG (3.5 ± 0.5 MBq, 100 ± 6 µg, 0.2 mL [mean ± SD]). Small-animal PET and microCT images were fused to calculate tumor uptake and compared with ex vivo biodistribution at 168 h after injection. ⁸⁹Zr- and ¹¹¹In-bevacizumab ex vivo biodistribution was compared at 24, 72, and 168 h after injection (2.0 ± 0.5 MBq each, 100 ± 4 µg in total, 0.2 mL). Results: Labeling efficiencies, radiochemical purity, stability, and binding properties were optimal for the radioimmunoconjugates. Small-animal PET showed uptake in well-perfused organs at 24 h and clear tumor localization from 72 h onward. Tumor uptake determined by quantification of small-animal PET images was higher for ⁸⁹Zr-bevacizumab—namely, 7.38 ± 2.06 %ID/g compared with 3.39 ± 1.16 %ID/g (percentage injected dose per gram) for human ⁸⁹Zr-IgG (P = 0.011) at 168 h and equivalent to ex vivo biodistribution studies. Tracer uptake in other organs was seen primarily in liver and spleen. ⁸⁹Zr- and ¹¹¹In-bevacizumab biodistribution was comparable. Conclusion: Radiolabeled bevacizumab showed higher uptake compared with radiolabeled human IgG in a human SKOV-3 ovarian tumor xenograft. Noninvasive quantitative small-animal PET was similar to invasive ex vivo biodistribution. Radiolabeled bevacizumab is a new tracer for noninvasive in vivo imaging of VEGF in the tumor microenvironment.

Key Words: VEGF • bevacizumab • small-animal PET • xenograft • in vivo

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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