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Characterization of the DNA interaction, performed with the non-radioactive Re and <jats:sup>127<\/jats:sup>I congeners, confirmed that all compounds act as DNA intercalators. Both classes of compounds induce double strand breaks (DSB) in plasmid DNA but the extent of DNA damage is strongly dependent on the linker between the Auger emitter (<jats:sup>99m<\/jats:sup>Tc or <jats:sup>125<\/jats:sup>I) and the AO moiety. The <jats:italic>in vitro<\/jats:italic> evaluation was complemented with molecular docking studies and Monte Carlo simulations of the energy deposited at the nanometric scale, which corroborated the experimental data. Two of the tested compounds, <jats:sup><jats:bold>125<\/jats:bold><\/jats:sup><jats:bold>I-C<\/jats:bold><jats:sub><jats:bold>5<\/jats:bold><\/jats:sub> and <jats:sup><jats:bold>99m<\/jats:bold><\/jats:sup><jats:bold>Tc-C<\/jats:bold><jats:sub><jats:bold>3<\/jats:bold><\/jats:sub>, place the corresponding radionuclide at similar distances to DNA and produce comparable DSB yields in plasmid and cellular DNA. These results provide the first evidence that <jats:sup>99m<\/jats:sup>Tc can induce DNA damage with similar efficiency to that of <jats:sup>125<\/jats:sup>I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of <jats:sup><jats:bold>99m<\/jats:bold><\/jats:sup><jats:bold>Tc-C<\/jats:bold><jats:sub><jats:bold>3<\/jats:bold><\/jats:sub> in tumoral cells suggests that <jats:sup>99m<\/jats:sup>Tc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the <jats:sup>125<\/jats:sup>I-labelled congeners.<\/jats:p>","DOI":"10.1038\/srep42544","type":"journal-article","created":{"date-parts":[[2017,2,13]],"date-time":"2017-02-13T10:20:37Z","timestamp":1486981237000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA"],"prefix":"10.1038","volume":"7","author":[{"given":"Edgar","family":"Pereira","sequence":"first","affiliation":[]},{"given":"Let\u00edcia","family":"do Quental","sequence":"additional","affiliation":[]},{"given":"Elisa","family":"Palma","sequence":"additional","affiliation":[]},{"given":"Maria Cristina","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Filipa","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Paula","family":"Raposinho","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Correia","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o","family":"Lavrado","sequence":"additional","affiliation":[]},{"given":"Salvatore","family":"Di Maria","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Belchior","sequence":"additional","affiliation":[]},{"given":"Pedro","family":"Vaz","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Ant\u00f3nio","family":"Paulo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2017,2,13]]},"reference":[{"key":"BFsrep42544_CR1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0001-2998(96)80020-1","volume":"26","author":"DV Becker","year":"1996","unstructured":"Becker, D. 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