C2TN Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
DECN-Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
Molecules. 2021 Jan 15;26(2):441. doi: 10.3390/molecules26020441.
For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. However, there is a growing body of evidence that other targets, such as the mitochondria, could be relevant subcellular targets in Auger therapy. Thus, we developed dual-targeted Tc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of Tc in the mitochondria, and a bombesin peptide to provide specificity towards the gastrin releasing peptide receptor (GRPr) overexpressed in prostate cancer cells. The designed dual-targeted complex, , is efficiently internalized by human prostate cancer PC3 cells through a specific GRPr-mediated mechanism of uptake. Moreover, the radioconjugate provided an augmented accumulation of Tc in the mitochondria of the target tumor cells, most probably following its intracellular cleavage by cathepsin B. In addition, showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner.
为了实现有效的 Auger 疗法治疗癌症，Auger 电子发射器必须被递送到肿瘤细胞附近的放射敏感细胞靶标。核 DNA 被认为是 Auger 电子产生增强放射毒性效应和显著细胞死亡的最相关靶标。然而，越来越多的证据表明，其他靶标，如线粒体，可能是 Auger 治疗中的相关亚细胞靶标。因此，我们开发了含有三苯基膦（TPP）部分的双靶向 Tc(I)三羰基配合物，以促进 Tc 在线粒体中的积累，以及一种蛙皮素肽，以提供对在前列腺癌细胞中过表达的胃泌素释放肽受体（GRPr）的特异性。设计的双靶向配合物 ， 通过特定的 GRPr 介导的摄取机制被人前列腺癌 PC3 细胞有效内化。此外，放射性结合物增加了 Tc 在靶肿瘤细胞线粒体中的积累，很可能是通过组织蛋白酶 B 的细胞内切割。此外， 以剂量依赖的方式显示出降低 PC3 细胞存活率的增强能力。
