Khosravifarsani Meysam, Ait-Mohand Samia, Paquette Benoit, Sanche Léon, Guérin Brigitte
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
Sherbrooke Molecular Imaging Center (CIMS), CRCHUS, 3001, 12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada.
J Med Chem. 2021 May 27;64(10):6765-6776. doi: 10.1021/acs.jmedchem.1c00039. Epub 2021 Apr 28.
Terpyridine platinum (TP)-based chemotherapeutic agents target three-dimensional structures on DNA known as G-quadruplexes. We report the rational design and synthesis of a TP conjugate combined with copper-64 (Cu), the decay characteristics of which include emission of β and Auger electrons for radiotherapy and β particles for positron emission tomography (PET) imaging. The present experimental studies show that the novel [Cu]Cu-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-TP is stable, permitting selective killing of cancer cells. The antitumor activity of [Cu]Cu-NOTA-TP at high apparent molar activity is in the low nanomolar range and 27,800-fold greater than that of Cu-NOTA-TP at 24 h post treatment. These results suggest that this combination of a cytotoxic TP agent with Cu has considerable potential for cancer treatment and PET imaging.
基于三联吡啶铂（TP）的化疗药物靶向DNA上被称为G-四链体的三维结构。我们报告了一种与铜-64（Cu）结合的TP共轭物的合理设计与合成，其衰变特性包括发射用于放射治疗的β和俄歇电子以及用于正电子发射断层扫描（PET）成像的β粒子。目前的实验研究表明，新型的[Cu]Cu-1,4,7-三氮杂环壬烷-1,4,7-三乙酸（NOTA）-TP是稳定的，能够选择性地杀死癌细胞。在高表观摩尔活性下，[Cu]Cu-NOTA-TP的抗肿瘤活性处于低纳摩尔范围，且在治疗后24小时比Cu-NOTA-TP高27800倍。这些结果表明，这种细胞毒性TP剂与Cu的组合在癌症治疗和PET成像方面具有相当大的潜力。
