Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin alpha(v)beta(3) and vascular endothelial growth factor

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 alpha(v)beta(3) 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 alpha(v)beta(3) 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 alpha(v)beta(3) and VEGF. Radiobiodistribution of Tc-99m-3PRGD2 and I-125-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 alpha(v)beta(3) 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.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000337286200019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Radiology, Nuclear Medicine & Medical ImagingSCI(E)PubMed7ARTICLEwangfan@bjmu.edu.cn; liuzf@bjmu.edu.cn71428-14394