TY - JOUR T1 - Uniformed intratumoral distribution of radioactivity produced by using two different radioagents <sup>64</sup>Cu-cyclam-RAFT-c(-RGDfK-)<sub>4</sub> and <sup>64</sup>Cu-ATSM improves therapeutic efficacy in a small animal tumor model JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1271 LP - 1271 VL - 59 IS - supplement 1 AU - Zhao-Hui Jin AU - Atsushi Tsuji AU - Mélissa Degardin AU - Aya Sugyo AU - Yukie Yoshii AU - Ming-Rong Zhang AU - Yasuhisa Fujibayashi AU - Pascal Dumy AU - Didier Boturyn AU - Tatsuya Higashi Y1 - 2018/05/01 UR - http://jnm.snmjournals.org/content/59/supplement_1/1271.abstract N2 - 1271Objectives: The present study proposed a new concept for targeted radionuclide therapy (TRT) to improve intratumoral radioactivity distribution using two different radiopharmaceuticals. For this, we examined the combined use of 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD) and 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), with the former accumulated in αVβ3 integrin-overexpressed angiogenic endothelial cells and tumor cells and the latter in hypoxic regions, in a small animal tumor model. Methods: Mice with subcutaneous αVβ3-positive U87MG-glioblastoma xenografts were used. Intratumoral distributions of “64Cu-RaftRGD” and 64Cu-ATSM were visualized by fluorescence imaging and autoradiography of coinjected a near-infrared dye Cy5.5-labeled RAFT-c(-RGDfK-)4 and 64Cu-ATSM at 3 h postinjection. The mice were treated with single intravenous administration of a vehicle solution as control, 18.5 or 37 MBq of 64Cu-RaftRGD or 64Cu-ATSM, or a combination (18.5 MBq for each agent), and tumor volume, tumor cell proliferation, body weight, and survival were assessed. Biodistribution assay was also performed for evaluating tumor and major organ uptakes. Results: The intratumoral distributions of Cy5.5-RaftRGD and 64Cu-ATSM were discordant and nearly complementary, leading to a more uniform radioactivity distribution with the combination of the radiolabeled two. Although neither of 64Cu-RaftRGD and 64Cu-ATSM at 18.5 MBq showed a significant effect on the tumor growth, the combined use of them (total injected dose of 37 MBq) demonstrated sustained inhibitory effects on tumor growth and tumor cell proliferation and produced prolonged survival of the mice. This was observed when compared with 37 MBq of either single agent. Interestingly, tumor uptake of the combination was lower than that of 64Cu-ATSM alone, although higher than that of 64Cu-RaftRGD. The organ showing the highest uptake was different between the kidneys for 64Cu-RaftRGD and the liver for 64Cu-ATSM. No obvious adverse effect was observed in all treated mice. Conclusion: The combination of 64Cu-RaftRGD and 64Cu-ATSM achieved a synergistic antitumor effect due to a more uniform radioactivity distribution over tumor. Combining different radiopharmaceuticals to improve intratumoral distribution would be a promising concept for more effective and safer TRT. ER -