Synthesis and Biological Evaluation of 99mTc(I) Tricarbonyl Complexes Dual-Targeted at Tumoral Mitochondria

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, <b> ^99mTc-TPP-BBN</b>, 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, <b> ^99mTc-TPP-BBN</b> showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner.