Dosimetry assessment of DNA damage by Auger-emitting radionuclides: Experimental and Monte Carlo studies

In order to study the dosimetric behavior of these two radionuclides (125I and 99mTc) at nano-scale sizes and given the DNA-intercalation properties of Acridine Orange (AO), we have designed 99mTc (I)-tricarbonyl complexes and 125I-heteroaromatic compounds that contain AO derivatives, in order to promote a closer proximity between the radionuclides and the DNA structure. With the aim to have an insight on the relevance of these radiolabelled compounds for DNA-targeted Auger therapy, different aspects were investigated: i) their ability to cause DNA strand breaks; ii) the influence of the two different radionuclides in DNA damage; iii) the effect of the distance between the AO intercalating unit and the radioactive atom (99mTc or 125I). To address these issues several studies were carried out encompassing the evaluation of plasmid DNA damage, molecular docking and nanodosimetric Monte Carlo modelling and calculations. Results show that the two classes of compounds are able to induce DNA double strand breaks (dsb), but the number of DNA damages (e.g. dsb yield) is strongly dependent on the linker used to attach the Auger emitting radionuclide (125I or 99mTc) to the AO moiety. In addition, nanodosimetric calculations confirm a strong gradient of the absorbed energy with the DNA-radionuclide distance for the two radionuclides studied. Finally these results show the existence of a critical distance (of about 11 Å) beyond which it is probable that the direct effects start to be ineffective in DNA damage induction.