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Abstract：
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 99mTc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of 99mTc 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,
99mTc-TPP-BBN, 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 99mTc in the mitochondria of the target tumor cells, most probably following its intracellular cleavage by cathepsin B. In addition,
99mTc-TPP-BBN showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner.
摘要：
为了有效治疗癌症，俄歇电子发射体必须被递送到紧邻放射敏感细胞靶标的肿瘤细胞。核DNA被认为是俄歇电子最相关的靶标，具有增强的放射性毒性作用和显着的细胞死亡。然而,越来越多的证据表明其他目标，比如线粒体，可能是俄歇疗法中的相关亚细胞靶标。因此，我们开发了双靶向99mTc（I）三羰基复合物，含有三苯基鳞（TPP）部分，以促进99mTc在线粒体中的积累，以及一种对过表达于前列腺癌细胞中的胃泌素释放肽受体(GRPr)提供特异性的蛙皮素肽。设计的双目标综合体，99mTc-TPP-BBN,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，放射性缀合物提供了99mTc在靶肿瘤细胞线粒体中的增加积累，很可能是在其被组织蛋白酶B细胞内裂解之后，99mTc-TPP-BBN显示出增强的降低PC3细胞存活的能力，以剂量依赖的方式。
