Département de chimie moléculaire

Objective: Copper-67 (Cu) is one of the most promising radionuclides for internal radiation therapy. Globally, several projects have recently been initiated for developing innovative approaches for the large-scale prodn. of Cu. Encouraged by these, we performed Cu-radiolabeling of a tetrameric cyclic Arg-Gly-Asp (cRGD) peptide conjugate, cyclam-RAFT-c(-RGDfK-)4, which selectively targets $\alpha$V$\beta$3 integrin ($\alpha$V$\beta$3), the transmembrane receptor involved in tumor invasion, angiogenesis, and metastasis. We also evaluated the therapeutic potential and safety of this radiocompound. Materials and methods: Cu, produced through the Ni($\alpha$, p)Cu reaction, was used for the radiolabeling of cyclam-RAFT-c(-RGDfK-)4 at 70°C for 10 min. The radiolabeling efficiency and product stability were assessed using reversed-phase high-performance liq. chromatog. and/or thin-layer chromatog. Mice with s.c. $\alpha$V$\beta$3-pos. U87MG-glioblastoma xenografts received a single i.v. injection of one of the following: Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq), peptide control, or vehicle soln. The tumor vols. were measured, side effects were assessed in terms of body wt., routine hematol., and hepatic and renal functions, and the mouse radiation dosimetry was estd. Results: Cu-cyclam-RAFT-c(-RGDfK-)4 was produced with a radiochem. purity of 97.9±2.4{%} and a specific activity of 2.7±0.6 MBq/nmol and showed high in-vitro and in-vivo plasma stability. The administration of a single dose of Cu-cyclam-RAFT-c(-RGDfK-)4 resulted in significant tumor growth delay in comparison with that obsd. upon vehicle or peptide control administration, with an estd. tumor-absorbed dose of 0.712 Gy. No significant toxicity was obsd. in Cu-cyclam-RAFT-c(-RGDfK-)4-treated mice. Conclusion: Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising therapeutic agent for $\alpha$V$\beta$3 integrin-targeted internal radiotherapy. [on SciFinder(R)]