title: Evaluation of 99mTc-Z IGF1R:4551-GGGC affibody molecule, a new probe for imaging of insulin-like growth factor type 1 receptor expression.
abstract: 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%). (99m)Tc-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. [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R: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-ZIGF1R:4551-GGGC than for [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551 at 4 h after injection. However, the liver uptake of (99m)Tc-ZIGF1R:4551-GGGC was 1.2- to 2-fold higher in comparison with [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551. A possible reason for the elevated hepatic uptake of (99m)Tc-ZIGF1R:4551-GGGC is a high lipophilicity of amino acids in the binding site of ZIGF1R:4551, which is not compensated in (99m)Tc-ZIGF1R:4551-GGGC. In conclusion, (99m)Tc-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.
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Mitran
authors.forename: Mohamed
authors.initials: M
authors.lastname: Altai
authors.forename: Camilla
authors.initials: C
authors.lastname: Hofström
authors.forename: Hadis
authors.initials: H
authors.lastname: Honarvar
authors.forename: Mattias
authors.initials: M
authors.lastname: Sandström
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Gräslund
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000494:pharmacology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013667:Technetium / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000597236:IGF1R protein, human; D009363:Neoplasm Proteins; D019275:Radiopharmaceuticals; D017451:Receptors, Somatomedin; D011993:Recombinant Fusion Proteins; D013667:Technetium; D017526:Receptor, IGF Type 1