Positron emission tomography imaging of tumor angiogenesis and monitoring of antiangiogenic efficacy using the novel tetrameric peptide probe 64Cu-cyclam-RAFT-c(-RGDfK-)4.
64Cu-cyclam-RAFT-c(-RGDfK-)4 is a novel multimeric positron emission tomography (PET) probe for αVβ3 integrin imaging. Its uptake and αVβ3 expression in tumors showed a linear correlation. Since αVβ3 integrin is strongly expressed on activated endothelial cells during angiogenesis, we aimed to determine whether 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used to image tumor angiogenesis and monitor the antiangiogenic effect of a novel multi-targeted tyrosine kinase inhibitor, TSU-68. Athymic nude mice bearing human hepatocellular carcinoma HuH-7 xenografts, which expressed negligible αVβ3 levels on the tumor cells, received intraperitoneal injections of TSU-68 or the vehicle for 14 days. Antiangiogenic effects were determined at the end of therapy in terms of 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake evaluated using PET, biodistribution assay, and autoradiography, and they were compared with microvessel density (MVD) determined by CD31 immunostaining. 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET enabled clear tumor visualization by targeting the vasculature, and the biodistribution assay indicated high tumor-to-blood and tumor-to-muscle ratios of 31.6 ± 6.3 and 6.7 ± 1.1, respectively, 3 h after probe injection. TSU-68 significantly slowed tumor growth and reduced MVD; these findings were consistent with a significant reduction in the tumor 64Cu-cyclam-RAFT-c(-RGDfK-)4 uptake. Moreover, a linear correlation was observed between tumor MVD and the corresponding standardized uptake value (SUV) (r = 0.829, P = 0.011 for SUV(mean); r = 0.776, P = 0.024 for SUV(max)) determined by quantitative PET. Autoradiography and immunostaining showed that the distribution of intratumoral radioactivity and tumor vasculature corresponded. We concluded that 64Cu-cyclam-RAFT-c(-RGDfK-)4 PET can be used for in vivo angiogenesis imaging and monitoring of tumor response to antiangiogenic therapy.
Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba, 263-8555, Japan. zhaohui@nirs.go.jp
Zhao-Hui
ZH
Jin
Takako
T
Furukawa
Michael
M
Claron
Didier
D
Boturyn
Jean-Luc
JL
Coll
Toshimitsu
T
Fukumura
Yasuhisa
Y
Fujibayashi
Pascal
P
Dumy
Tsuneo
T
Saga
D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D015335:Molecular Probes; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
D003301:Copper Radioisotopes; D015335:Molecular Probes