Oroujeni Maryam, Garousi Javad, Andersson Ken G, Löfblom John, Mitran Bogdan, Orlova Anna, Tolmachev Vladimir
Department of Immunology, Genetics and Pathology, Uppsala University, SE- 751 85 Uppsala, Sweden.
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SE- 106 91 Stockholm, Sweden.
Cells. 2018 Sep 18;7(9):141. doi: 10.3390/cells7090141.
Radionuclide imaging of epidermal growth factor receptor (EGFR) expression in tumors may stratify patients for EGFR-targeting therapies and predict response or resistance to certain treatments. Affibody molecules, which are nonimmunoglobulin scaffold proteins, have a high potential as probes for molecular imaging. In this study, maleimido derivative of desferrioxamine B (DFO) chelator was site-specifically coupled to the C-terminal cysteine of the anti-EGFR affibody molecule ZEGFR:2377, and the DFO-ZEGFR:2377 conjugate was labeled with the generator-produced positron-emitting radionuclide Ga. Stability, specificity of binding to EGFR-expressing cells, and processing of [Ga]Ga-DFO-ZEGFR:2377 by cancer cells after binding were evaluated in vitro. In vivo studies were performed in nude mice bearing human EGFR-expressing A431 epidermoid cancer xenografts. The biodistribution of [Ga]Ga-DFO-ZEGFR:2377 was directly compared with the biodistribution of [Zr]Zr-DFO-ZEGFR:2377.
DFO-ZEGFR: 2377 was efficiently (isolated yield of 73 ± 3%) and stably labeled with Ga. Binding of [Ga]Ga-DFO-ZEGFR:2377 to EGFR-expressing cells in vitro was receptor-specific and proportional to the EGFR expression level. In vivo saturation experiment demonstrated EGFR-specific accumulation of [Ga]Ga-DFO-ZEGFR:2377 in A431 xenografts. Compared to [Zr]Zr-DFO-ZEGFR:2377, [Ga]Ga-DFO-ZEGFR:2377 demonstrated significantly ( < 0.05) higher uptake in tumors and lower uptake in spleen and bones. This resulted in significantly higher tumor-to-organ ratios for [Ga]Ga-DFO-ZEGFR:2377. In conclusion, [Ga]Ga-DFO-ZEGFR:2377 is a promising probe for imaging of EGFR expression.
肿瘤中表皮生长因子受体（EGFR）表达的放射性核素成像可对患者进行分层，以接受EGFR靶向治疗，并预测对某些治疗的反应或耐药性。亲和体分子是非免疫球蛋白支架蛋白，具有作为分子成像探针的巨大潜力。在本研究中，去铁胺B（DFO）螯合剂的马来酰亚胺衍生物位点特异性地偶联到抗EGFR亲和体分子ZEGFR:2377的C末端半胱氨酸上，并且用发生器产生的发射正电子的放射性核素镓标记DFO-ZEGFR:2377共轭物。在体外评估了[镓]Ga-DFO-ZEGFR:2377的稳定性、与表达EGFR的细胞结合的特异性以及结合后癌细胞对其的处理情况。在携带人EGFR表达的A431表皮样癌异种移植瘤的裸鼠中进行了体内研究。直接比较了[镓]Ga-DFO-ZEGFR:2377与[锆]Zr-DFO-ZEGFR:2377的生物分布。
DFO-ZEGFR:2377被镓高效（分离产率为73±3%）且稳定地标记。[镓]Ga-DFO-ZEGFR:2377在体外与表达EGFR的细胞的结合是受体特异性的，并且与EGFR表达水平成比例。体内饱和实验证明[镓]Ga-DFO-ZEGFR:2377在A431异种移植瘤中特异性积累。与[锆]Zr-DFO-ZEGFR:2377相比，[镓]Ga-DFO-ZEGFR:2377在肿瘤中的摄取显著更高（<0.05），而在脾脏和骨骼中的摄取更低。这导致[镓]Ga-DFO-ZEGFR:2377的肿瘤与器官比值显著更高。总之，[镓]Ga-DFO-ZEGFR:2377是一种用于EGFR表达成像的有前景的探针。
