Data from α<sub>V</sub>β<sub>3</sub> Integrin-Targeted Radionuclide Therapy with <sup>64</sup>Cu-cyclam-RAFT-c(-RGDfK-)<sub>4</sub>

The transmembrane cell adhesion receptor α_Vβ₃ integrin (α_Vβ₃) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide–based radiotracer ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄, which successfully captured α_Vβ₃-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established α_Vβ₃-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ with ascending peptide doses (0.25–10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes–24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄, respectively. Peptide dose study showed that the tumor uptake of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ dose dependently decreased at doses ≥1 nmol, indicating a saturation of α_Vβ₃ with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37–74 MBq of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄. Our study demonstrates the therapeutic efficacy and safety of ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ for α_Vβ₃-targeted radionuclide therapy. ⁶⁴Cu-cyclam-RAFT-c(-RGDfK-)₄ would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076–85. ©2016 AACR.