Gé Lorraine Gaenaelle, Danielsen Mathias Bogetoft, Nielsen Aaraby Yoheswaran, Skavenborg Mathias Lander, Langkjær Niels, Thisgaard Helge, McKenzie Christine J
Department of Nuclear Medicine, Odense University Hospital, Kloevervaenget 47, 5000 Odense C, Denmark.
Department of Clinical Research, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
Molecules. 2025 Jan 7;30(2):212. doi: 10.3390/molecules30020212.
The overexpression of the epidermal growth factor receptor (EGFR) in certain types of prostate cancers and glioblastoma makes it a promising target for targeted radioligand therapy. In this context, pairing an EGFR-targeting peptide with the emerging theranostic pair comprising the Auger electron emitter cobalt-58m (Co) and the Positron Emission Tomography-isotope cobalt-55 (Co) would be of great interest for creating novel radiopharmaceuticals for prostate cancer and glioblastoma theranostics. In this study, GE11 (YHWYGYTPQNVI) was investigated for its EGFR-targeting potential when conjugated using click chemistry to N1-((triazol-4-yl)methyl)-N1,N2,N2-tris(pyridin-2-ylmethyl)ethane-1,2-diamine (TZTPEN). This chelator is suitable for binding Co and Co. With cobalt-57 (Co) serving as a surrogate radionuclide for Co, the novel GE11-TZTPEN construct was successfully radiolabeled with a high radiochemical yield (99%) and purity (>99%). [Co]Co-TZTPEN-GE11 showed high stability in PBS (pH 5) and specific uptake in EGFR-positive cell lines. Disappointingly, no tumor uptake was observed in EGFR-positive tumor-bearing mice, with most activity being accumulated predominantly in the liver, gall bladder, kidneys, and spleen. Some bone uptake was also observed, suggesting in vivo dissociation of Co from the complex. In conclusion, [Co]Co-TZTPEN-GE11 shows poor pharmacokinetics in a mouse model and is, therefore, not deemed suitable as a targeting radiopharmaceutical for EGFR.
表皮生长因子受体（EGFR）在某些类型的前列腺癌和胶质母细胞瘤中过表达，这使其成为靶向放射性配体治疗的一个有前景的靶点。在这种情况下，将靶向EGFR的肽与新兴的治疗诊断对（包括俄歇电子发射体钴 - 58m（⁵⁸mCo）和正电子发射断层扫描同位素钴 - 55（⁵⁵Co））配对，对于开发用于前列腺癌和胶质母细胞瘤治疗诊断的新型放射性药物将非常有意义。在本研究中，研究了GE11（YHWYGYTPQNVI）在通过点击化学与N1 - （（三唑 - 4 - 基）甲基） - N1，N2，N2 - 三（吡啶 - 2 - 基甲基）乙烷 - 1，2 - 二胺（TZTPEN）偶联时的EGFR靶向潜力。这种螯合剂适用于结合⁵⁸mCo和⁵⁵Co。以钴 - 57（⁵⁷Co）作为⁵⁸mCo的替代放射性核素，新型GE11 - TZTPEN构建体成功地以高放射化学产率（99%）和纯度（>99%）进行了放射性标记。[⁵⁸mCo]Co - TZTPEN - GE11在磷酸盐缓冲盐水（pH 5）中显示出高稳定性，并在EGFR阳性细胞系中具有特异性摄取。令人失望的是，在携带EGFR阳性肿瘤的小鼠中未观察到肿瘤摄取，大部分活性主要积聚在肝脏、胆囊、肾脏和脾脏中。还观察到一些骨摄取，表明⁵⁸mCo在体内从复合物中解离。总之，[⁵⁸mCo]Co - TZTPEN - GE11在小鼠模型中显示出较差的药代动力学，因此，不被认为适合作为EGFR的靶向放射性药物。
