Abstract
Purpose
Optical imaging is emerging as a powerful tool for the noninvasive imaging of the biological processes in living subjects. This study aimed to investigate whether optical imaging of integrin αvβ3 and vascular endothelial growth factor (VEGF) expression can serve as sensitive biomarkers for tumor early response to antiangiogenic therapy.
Methods
We synthesized two near-infrared fluorescence (NIRF) imaging agents, CF680R-3PRGD2 and CF750-BevF(ab')2, which were designed to specifically bind to integrin αvβ3 and VEGF, respectively. The ability of optical imaging using the two imaging agents for early monitoring the antiangiogenic effect of sunitinib was evaluated.
Results
CF680R-3PRGD2 and CF750-BevF(ab')2 specifically bound to their respective targets in vitro and in HT-29 tumor-bearing nude mice. Sunitinib treatment led to significantly decreased tumor uptake of CF680R-3PRGD2 (e.g., 7.47 ± 1.62 % vs. 4.24 ± 0.16 % on day 4; P < 0.05) and CF750-BevF(ab')2 (e.g., 7.43 ± 2.43 % vs. 4.04 ± 1.39 % on day 2; P < 0.05) in vivo. Immunofluorescence staining and an enzyme-linked immunosorbent assay confirmed that sunitinib-induced changes in tumor uptake of CF680R-3PRGD2 and CF750-BevF(ab')2 were correlated with changes in the levels of integrin αvβ3 and VEGF. Radiobiodistribution of 99mTc-3PRGD2 and 125I-BevF(ab')2, the radiocounterparts of CF680R-3PRGD2 and CF750-BevF(ab')2, respectively, also validated optical imaging results.
Conclusion
Longitudinal monitoring of tumor integrin αvβ3 and VEGF expression could be used as early biomarkers for tumor response to antiangiogenic therapy. This strategy may facilitate the development of new antiangiogenic drugs, and be used for elucidation of the underlying mechanisms of therapies involving the integrin and the VEGF signaling pathway.
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Acknowledgments
This work was supported, in part, by the National Natural Science Foundation of China (NSFC) projects (81222019, 81125011, and 81000625), “973” projects (2013CB733802 and 2011CB707703), grants from the Ministry of Science and Technology of China (2011YQ030114, 2012ZX09102301, and 2012BAK25B03), grants from the Ministry of Education of China (31300 and BMU20110263), grants from the Beijing Natural Science Foundation (7132131 and 7132123), and a grant from the Beijing Nova Program (Z121107002512010).
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The authors declare that they have no conflict of interest.
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Sun, X., Ma, T., Liu, H. et al. Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin αvβ3 and vascular endothelial growth factor. Eur J Nucl Med Mol Imaging 41, 1428–1439 (2014). https://doi.org/10.1007/s00259-014-2702-1
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DOI: https://doi.org/10.1007/s00259-014-2702-1