Iodine 125‐labeled mesenchymal–epithelial transition factor binding peptide‐click‐cRGDyk heterodimer for glioma imaging

• Published in: Cancer science Vol. 102; no. 8; pp. 1516 - 1521
• Main Authors: Kim, Eun‐Mi, Jeong, Min‐Hee, Kim, Dong Wook, Jeong, Hwan‐Jeong, Lim, Seok Tae, Sohn, Myung‐Hee
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2011; Blackwell
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brain Neoplasms - diagnostic imaging; Carrier Proteins - metabolism; Click Chemistry; Female; Glioma - diagnostic imaging; Iodine Radioisotopes; Medical sciences; Mice; Neurology; Original; Peptides, Cyclic - metabolism; Protein Multimerization; Proto-Oncogene Proteins c-met - metabolism; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Tumors; Tumors of the nervous system. Phacomatoses; Nervous system diseases; Cancerology; Glioma; Peptides; Central nervous system disease; Tumor; Medical imagery; Mesenchymal cell; Radioisotope; Heterodimer
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/j.1349-7006.2011.01983.x

In our previous study, mesenchymal–epithelial transition factor (c‐Met)‐binding peptides (cMBP) had been readily radiolabeled with radioactive iodide for glioma imaging because of five histidine amino acids. However, iodinated cMBP showed relatively unfavorable in vivo kinetics. For this reason, we tried to design dual peptide ligands that would be advantageous in recognizing both c‐Met receptor and integrin αvβ3. A cMBP‐click‐cRGDyk (cyclic Arg‐Gly‐Asp‐Tyr‐Lys) heterodimer was synthesized from mini polyethylene glycol‐conjugated cMBP‐3 glycine (GGG)‐a single name of amino acids (SC) (Ser‐Cys) and cRGDyk through a click (1 + 3 cycloaddition), and then labeled with iodine 125 (I‐125) via histidine in the cMBP and tyrosine in the cRGDyk. The receptor‐binding characteristics and tumor‐targeting efficacy of cMBP‐click‐cRGDyk were tested in vitro and in vivo. A cMBP‐click‐cRGDyk had comparable integrin αvβ3‐binding affinity with cRGDyk. The results of the biodistribution of 125I‐cMBP‐click‐cRGDyk at 4 h showed higher tumor‐to‐blood, tumor‐to‐liver, and tumor‐to‐muscle ratios: 10.07, 6.76, and 11.12, compared to 2.34, 1.99, and 5.18 of 125I‐cMBP‐GGG‐SC, respectively. U87MG tumor xenografts could be visualized by single photon emission computed tomography (SPECT)/CT using 125I‐cMBP‐click‐cRGDyk and also image contrast and overall quality were improved compared to 125I‐cMBP‐GGG‐SC. As the results of in vivo inhibition using free cRGDyk or cMBP‐GGG‐SC indicated, the tumoral uptake of 125I‐cMBP‐click‐cRGDyk decreased. This finding means that 125I‐cMBP‐click‐cRGDyk was specifically uptaken by integrin αvβ3 and the c‐Met receptor. Although imaging quality was improved, additional experiments are needed to acquire significant image‐quality improvement. (Cancer Sci 2011; 102: 1516–1521)