Strand Joanna, Nordeman Patrik, Honarvar Hadis, Altai Mohamed, Orlova Anna, Larhed Mats, Tolmachev Vladimir
Biomedical Radiation Sciences, Faculty of Medicine, Uppsala University 751 85, Uppsala, Sweden.
Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University 751 23, Uppsala, Sweden.
ChemistryOpen. 2015 Apr;4(2):174-82. doi: 10.1002/open.201402097. Epub 2015 Jan 12.
Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of (125)I-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type 2 (HER2) Affibody molecule (ZHER2:2395) was labeled using (125)I-IPEM with an overall yield of 45±3 %. (125)I-IPEM-ZHER2:2395 bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of (125)I-IPEM-ZHER2:2395 (24±2 and 5.7±0.3 % IA g(-1)at 1 and 4 h after injection, respectively) was significantly lower than uptake of (125)I-IHPEM-ZHER2:2395 (50±8 and 12±2 % IA g(-1)at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.
亲和体分子是基于小型支架的亲和蛋白，作为基于放射性核素的分子成像探针具有良好的特性。然而，放射性标记的亲和体分子在肾脏中的高重吸收是一个问题。我们已经表明，使用（125）I-3-碘-（（4-羟基苯基）乙基）马来酰亚胺（IHPEM）对含半胱氨酸的亲和体分子进行位点特异性标记可实现高肿瘤摄取，但肾脏中的放射性保留较低。我们假设使用4-碘苯乙基马来酰亚胺（IPEM）会因放射性代谢物的更高亲脂性而进一步降低肾脏中的放射性保留。使用（125）I-IPEM对一种抗人表皮生长因子受体2（HER2）亲和体分子（ZHER2:2395）进行标记，总产率为45±3％。（125）I-IPEM-ZHER2:2395特异性结合表达HER2的人卵巢癌细胞（SKOV-3细胞系）。在NMRI小鼠中，（125）I-IPEM-ZHER2:2395的肾脏摄取（注射后1小时和4小时分别为24±2和5.7±0.3％IA g-1）明显低于（125）I-IHPEM-ZHER2:2395的摄取（注射后1小时和4小时分别为50±8和12±2％IA g-1）。总之，使用更具亲脂性的连接子对亲和体分子进行放射性碘化可降低肾脏放射性。
