Département de chimie moléculaire

The transmembrane cell adhesion receptor $\alpha$V$\beta$3 integrin ($\alpha$V$\beta$3) has been identified as an important mol. 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 $\alpha$V$\beta$3-pos. tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established $\alpha$V$\beta$3-pos. tumor mouse model. Mice with s.c. 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 soln. and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body wt., routine hematol., 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 detd. at 3 h and at various time points (2 min-24 h) postinjection, resp., based on which radiation-absorbed doses were estd. 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, resp. Peptide dose study showed that the tumor uptake of 64Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a satn. of $\alpha$V$\beta$3 with the administered therapeutic doses (1 and 2 nmol). Combined anal. 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 $\alpha$V$\beta$3-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. [on SciFinder(R)]