title: Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA.
abstract: A new family of99mTc(I)- tricarbonyl complexes and125I-heteroaromatic compounds bearing an acridine orange (AO) DNA targeting unit was evaluated for Auger therapy. Characterization of the DNA interaction, performed with the non-radioactive Re and127I 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 (99mTc or125I) and the AO moiety. The in vitro 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,125I-C5and99mTc-C3, 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 that99mTc can induce DNA damage with similar efficiency to that of125I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of99mTc-C3in tumoral cells suggests that99mTc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the125I-labelled congeners.
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Edgar
authors.initials: E
authors.lastname: Pereira
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Letícia
authors.initials: L
authors.lastname: do Quental
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.|Centro Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1049-001 Lisboa, Portugal.
authors.forename: Elisa
authors.initials: E
authors.lastname: Palma
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Mendes
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Raposinho
authors.affiliation: Centro Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1049-001 Lisboa, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correia
authors.affiliation: iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Lavrado
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maria
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Belchior
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Vaz
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.affiliation: Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Paulo
mesh_terms: D000165:Acridine Orange / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004355:Drug Stability; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000627:therapeutic use; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009010:Monte Carlo Method; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D013057:Spectrum Analysis; D013667:Technetium / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D013667:Technetium; D004247:DNA; D000165:Acridine Orange; C000614960:Iodine-125