Evaluation of (99m)Tc-Z(IGF1R:4551)-GGGC affibody molecule, a new probe for imaging of insulin-like growth factor type 1 receptor expression

Overexpression of insulin-like growth factor-1 receptor (IGF-1R) in several cancers is associated with resistance to therapy. Radionuclide molecular imaging of IGF-1R expression in tumors may help in selecting the patients that will potentially respond to IGF-1R-targeted therapy. Affibody molecules are small (7 kDa) non-immunoglobulin-based scaffold proteins that are well-suited probes for radionuclide imaging. The aim of this study was the evaluation of an anti-IGF-1R affibody molecule labeled with technetium-99m using cysteine-containing peptide-based chelator GGGC at C-terminus. Z(IGF1R:4551)-GGGC was efficiently and stably labeled with technetium-99m (radiochemical yield 97 ± 3 %). (99m)Tc-Z(IGF1R:4551)-GGGC demonstrated specific binding to IGF-1R-expressing DU-145 (prostate cancer) and MCF-7 (breast cancer) cell lines and slow internalization in vitro. The tumor-targeting properties were studied in BALB/c nu/nu mice bearing DU-145 and MCF-7 xenografts. [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) was used for comparison. The biodistribution study demonstrated high tumor-to-blood ratios (6.2 ± 0.9 and 6.9 ± 1.0, for DU-145 and MCF-7, respectively, at 4 h after injection). Renal radioactivity concentration was 16-fold lower for (99m)Tc-Z(IGF1R:4551)-GGGC than for [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) at 4 h after injection. However, the liver uptake of (99m)Tc-Z(IGF1R:4551)-GGGC was 1.2- to 2-fold higher in comparison with [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551). A possible reason for the elevated hepatic uptake of (99m)Tc-Z(IGF1R:4551)-GGGC is a high lipophilicity of amino acids in the binding site of Z(IGF1R:4551), which is not compensated in (99m)Tc-Z(IGF1R:4551)-GGGC. In conclusion, (99m)Tc-Z(IGF1R:4551)-GGGC can visualize the IGF-1R expression in human tumor xenografts and provides low retention of radioactivity in kidneys. Further development of this imaging agent should include molecular design aimed at reducing the hepatic uptake.