title: Longitudinal monitoring of tumor antiangiogenic therapy with near-infrared fluorophore-labeled agents targeted to integrin αvβ3 and vascular endothelial growth factor.
abstract: OBJECTIVE
  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 (99m)Tc-3PRGD2 and (125)I-BevF(ab')2, the radiocounterparts of CF680R-3PRGD2 and CF750-BevF(ab')2, respectively, also validated optical imaging results.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Medical Isotopes Research Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China.
authors.forename: Xianlei
authors.initials: X
authors.lastname: Sun
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Xinhe
authors.initials: X
authors.lastname: Yu
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Huiyun
authors.initials: H
authors.lastname: Zhao
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D005456:Fluorescent Dyes / Q000378:metabolism; D005909:Glioblastoma / Q000098:blood supply / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007259:Infrared Rays; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008137:Longitudinal Studies; D051379:Mice; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D061848:Optical Imaging; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D005456:Fluorescent Dyes; D007211:Indoles; D039302:Integrin alphaVbeta3; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib