Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus

Although Tc-99m is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available "model" radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates Tc-99m-TPP-BBN and Tc-99m-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. Tc-99m-TPP-BBN and Tc-99m-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener Tc-99m-BBN, leading to an augmented formation of gamma H2AX foci and micronuclei. Tc-99m-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of Tc-99m-TPP-BBN in the mitochondria and enhanced uptake of Tc-99m-AO-BBN in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by Tc-99m. In particular, the results obtained for Tc-99m-TPP-BBN reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates.