Radiobiological and dosimetric assessment of DNA-intercalated (99m)Tc-complexes bearing acridine orange derivatives

BACKGROUND: Recently, a new family of (99m)Tc(I)-tricarbonyl complexes bearing an acridine orange (AO) DNA targeting unit and different linkers between the Auger emitter ((99m)Tc) and the AO moiety was evaluated for Auger therapy. Among them, (99m)Tc-C(3) places the corresponding radionuclide at a shortest distance to DNA and produces important double strand breaks (DSB) yields in plasmid DNA providing the first evidence that (99m)Tc can efficiently induce DNA damage when well positioned to the double helix. Here in, we have extended the studies to human prostate cancer PC3 cells using the (99m)Tc-C(3) and (99m)Tc-C(5) complexes, aiming to assess how the distance to DNA influences the radiation-induced biological effects in this tumoral cell line, namely, in which concerns early and late damage effects. RESULTS: Our results highlight the limited biological effectiveness of Auger electrons, as short path length radiation, with increasing distances to DNA. The evaluation of the radiation-induced biological effects was complemented with a comparative microdosimetric study based on intracellular dose values. The comparative study, between MIRD and Monte Carlo (MC) methods used to assess the cellular doses, revealed that efforts should be made in order to standardize the bioeffects modeling for DNA-incorporated Auger electron emitters. CONCLUSIONS: (99m)Tc might not be the ideal radionuclide for Auger therapy but can be useful to validate the design of new classes of Auger-electron emitting radioconjugates. In this context, our results highlight the crucial importance of the distance of Auger electron emitters to the target DNA and encourage the development of strategies for the fine tuning of the distance to DNA for other medical radionuclides (e.g., (111)In or (161)Tb) in order to enhance their radiotherapeutic effects within the Auger therapy of cancer.