Su Xinhui, Cheng Kai, Liu Yang, Hu Xiang, Meng Shuxian, Cheng Zhen
Department of Nuclear Medicine, Zhongshan Hospital Xiamen University, Xiamen, China.
Amino Acids. 2015 Jul;47(7):1409-19. doi: 10.1007/s00726-015-1975-4. Epub 2015 Apr 9.
The insulin-like growth factor 1 receptor (IGF-1R) serves as an attractive target for cancer molecular imaging and therapy. Previous single photon emission computerized tomography (SPECT) studies showed that the IGF-1R-targeting Affibody molecules (99m)Tc-ZIGF1R:4551-GGGC, (99m)Tc(CO)3-(HE)3-ZIGF1R:4551 and (111)In-DOTA-ZIGF1R:4551 can discriminate between high and low IGF-1R-expression tumors and have the potential for patient selection for IGF-1R-targeted therapy. Compared with SPECT, positron emission tomography (PET) may improve imaging of IGF-1R-expression, because of its high sensitivity, high spatial resolution, strong quantification ability. The aim of the present study was to develop the (64)Cu-labeled NOTA-conjugated Affibody molecule ZIGF-1R:4:40 as a PET probe for imaging of IGF-1R-positive tumor. An Affibody analogue (Ac-Cys-ZIGF-1R:4:40) binding to IGF-1R was site-specifically conjugated with NOTA and labeled with (64)Cu. Binding affinity and specificity of (64)Cu-NOTA-ZIGF-1R:4:40 to IGF-1R were evaluated using human glioblastoma U87MG cells. Small-animal PET, biodistribution, and metabolic stability studies were conducted on mice bearing U87MG xenografts after the injection of (64)Cu-NOTA-ZIGF-1R:4:40 with or without co-injection of unlabeled Affibody proteins. The radiosynthesis of (64)Cu-NOTA-ZIGF-1R:4:40 was completed successfully within 60 min with a decay-corrected yield of 75 %. (64)Cu-NOTA-ZIGF-1R:4:40 bound to IGF-1R with low nanomolar affinity (K D = 28.55 ± 3.95 nM) in U87MG cells. (64)Cu-NOTA-ZIGF-1R:4:40 also displayed excellent in vitro and in vivo stability. In vivo biodistribution and PET studies demonstrated targeting of U87MG gliomas xenografts was IGF-1R specific. The tumor uptake was 5.08 ± 1.07 %ID/g, and the tumor to muscle ratio was 11.89 ± 2.16 at 24 h after injection. Small animal PET imaging studies revealed that (64)Cu-NOTA-ZIGF-1R:4:40 could clearly identify U87MG tumors with good contrast at 1-24 h after injection. This study demonstrates that (64)Cu-NOTA-ZIGF-1R:4:40 is a promising PET probe for imaging IGF-1R positive tumor.
胰岛素样生长因子1受体（IGF-1R）是癌症分子成像和治疗的一个有吸引力的靶点。先前的单光子发射计算机断层扫描（SPECT）研究表明，靶向IGF-1R的亲合体分子（99m）Tc-ZIGF1R:4551-GGGC、(99m)Tc(CO)3-(HE)3-ZIGF1R:4551和（111）In-DOTA-ZIGF1R:4551能够区分高IGF-1R表达和低IGF-1R表达的肿瘤，并且有潜力用于选择适合IGF-1R靶向治疗的患者。与SPECT相比，正电子发射断层扫描（PET）可能会改善IGF-1R表达的成像，因为它具有高灵敏度、高空间分辨率和强大的定量能力。本研究的目的是开发（64）Cu标记的NOTA偶联亲合体分子ZIGF-1R:4:40作为用于IGF-1R阳性肿瘤成像的PET探针。将与IGF-1R结合的亲合体类似物（Ac-Cys-ZIGF-1R:4:40）与NOTA进行位点特异性偶联，并用（64）Cu进行标记。使用人胶质母细胞瘤U87MG细胞评估（64）Cu-NOTA-ZIGF-1R:4:40对IGF-1R的结合亲和力和特异性。在注射（64）Cu-NOTA-ZIGF-1R:4:40（伴或不伴未标记亲合体蛋白的共注射）后，对携带U87MG异种移植瘤的小鼠进行小动物PET、生物分布和代谢稳定性研究。（64）Cu-NOTA-ZIGF-1R:4:40的放射性合成在60分钟内成功完成，衰变校正产率为75%。在U87MG细胞中，（64）Cu-NOTA-ZIGF-1R:4:40以低纳摩尔亲和力（KD = 28.55 ± 3.95 nM）与IGF-1R结合。（64）Cu-NOTA-ZIGF-1R:4:40在体外和体内也表现出优异的稳定性。体内生物分布和PET研究表明，U87MG胶质瘤异种移植瘤的靶向是IGF-1R特异性的。注射后24小时，肿瘤摄取为5.08 ± 1.07%ID/g，肿瘤与肌肉的比值为11.89 ± 2.16。小动物PET成像研究表明，（64）Cu-NOTA-ZIGF-1R:4:40在注射后1至24小时能够以良好的对比度清晰识别U87MG肿瘤。本研究表明，（64）Cu-NOTA-ZIGF-1R:4:40是一种用于IGF-1R阳性肿瘤成像的有前景的PET探针。
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