Department of Radiation Oncology, J. Bruce Henrisken Cancer Research Laboratories, University of Nebraska Medical Center, 986850 Nebraska Medical Center, Omaha, Nebraska 68198-6850, USA.
J Med Chem. 2012 Mar 22;55(6):2649-71. doi: 10.1021/jm201482p. Epub 2012 Mar 8.
Targeted molecular radiotherapy opens unprecedented opportunities to eradicate cancer cells with minimal irradiation of normal tissues. Described in this study are radioactive cyclosaligenyl monophosphates designed to deliver lethal doses of radiation to cancer cells. These compounds can be radiolabeled with SPECT- and PET-compatible radionuclides as well as radionuclides suitable for Auger electron therapies. This characteristic provides an avenue for the personalized and comprehensive treatment strategy that comprises diagnostic imaging to identify sites of disease, followed by the targeted molecular radiotherapy based on the imaging results. The developed radiosynthetic methods produce no-carrier-added products with high radiochemical yield and purity. The interaction of these compounds with their target, butyrylcholinesterase, depends on the stereochemistry around the P atom. IC(50) values are in the nanomolar range. In vitro studies indicate that radiation doses delivered to the cell nucleus are sufficient to kill cells of several difficult to treat malignancies including glioblastoma and ovarian and colorectal cancers.
靶向分子放疗为消除癌细胞提供了前所未有的机会，同时最大限度地减少对正常组织的照射。本研究中描述的放射性环沙林基单磷酸酯旨在向癌细胞提供致死剂量的辐射。这些化合物可以用 SPECT 和 PET 相容的放射性核素以及适合俄歇电子治疗的放射性核素进行放射性标记。这一特点为个性化和全面的治疗策略提供了途径，包括诊断成像以识别疾病部位，然后根据成像结果进行靶向分子放疗。所开发的放射合成方法可产生高放射化学产率和纯度的无载体添加产物。这些化合物与其靶标丁酰胆碱酯酶的相互作用取决于 P 原子周围的立体化学。IC(50) 值在纳摩尔范围内。体外研究表明，递送到细胞核的辐射剂量足以杀死包括神经胶质瘤和卵巢癌、结直肠癌在内的几种难以治疗的恶性肿瘤的细胞。
