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

Mitran, Bogdan, Altai, Mohamed, Hofström, Camilla, Honarvar, Hadis, Sandström, Mattias, Orlova, Anna, Tolmachev, Vladimir, Gräslund, Torbjörn
Amino acids 2015 v.47 no.2 pp. 303-315
amino acids, binding sites, breast neoplasms, chelating agents, humans, hydrophobicity, image analysis, insulin-like growth factor I receptor, kidneys, liver, mice, patients, prostatic neoplasms, scaffolding proteins, scintigraphy, somatomedins, therapeutics
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. ZIGF₁R:₄₅₅₁-GGGC was efficiently and stably labeled with technetium-99m (radiochemical yield 97 ± 3 %).⁹⁹ᵐTc-ZIGF₁R: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. [⁹⁹ᵐTc(CO)₃]⁺-(HE)₃-ZIGF₁R:₄₅₅₁was 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 for⁹⁹ᵐTc-ZIGF₁R:₄₅₅₁-GGGC than for [⁹⁹ᵐTc(CO)₃]⁺-(HE)₃-ZIGF₁R:₄₅₅₁at 4 h after injection. However, the liver uptake of⁹⁹ᵐTc-ZIGF₁R:₄₅₅₁-GGGC was 1.2- to 2-fold higher in comparison with [⁹⁹ᵐTc(CO)₃]⁺-(HE)₃-ZIGF₁R:₄₅₅₁. A possible reason for the elevated hepatic uptake of⁹⁹ᵐTc-ZIGF₁R:₄₅₅₁-GGGC is a high lipophilicity of amino acids in the binding site of ZIGF₁R:₄₅₅₁, which is not compensated in⁹⁹ᵐTc-ZIGF₁R:₄₅₅₁-GGGC. In conclusion,⁹⁹ᵐTc-ZIGF₁R: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.