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Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA

A new family of (99m)Tc(I)- tricarbonyl complexes and (125)I-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 and (127)I congeners, confirmed that all compounds...

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Autores principales: Pereira, Edgar, do Quental, Letícia, Palma, Elisa, Oliveira, Maria Cristina, Mendes, Filipa, Raposinho, Paula, Correia, Isabel, Lavrado, João, Di Maria, Salvatore, Belchior, Ana, Vaz, Pedro, Santos, Isabel, Paulo, António
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304164/
https://www.ncbi.nlm.nih.gov/pubmed/28211920
http://dx.doi.org/10.1038/srep42544
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author Pereira, Edgar
do Quental, Letícia
Palma, Elisa
Oliveira, Maria Cristina
Mendes, Filipa
Raposinho, Paula
Correia, Isabel
Lavrado, João
Di Maria, Salvatore
Belchior, Ana
Vaz, Pedro
Santos, Isabel
Paulo, António
author_facet Pereira, Edgar
do Quental, Letícia
Palma, Elisa
Oliveira, Maria Cristina
Mendes, Filipa
Raposinho, Paula
Correia, Isabel
Lavrado, João
Di Maria, Salvatore
Belchior, Ana
Vaz, Pedro
Santos, Isabel
Paulo, António
author_sort Pereira, Edgar
collection PubMed
description A new family of (99m)Tc(I)- tricarbonyl complexes and (125)I-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 and (127)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 ((99m)Tc or (125)I) 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, (125)I-C(5) and (99m)Tc-C(3), 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 (99m)Tc can induce DNA damage with similar efficiency to that of (125)I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of (99m)Tc-C(3) in tumoral cells suggests that (99m)Tc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the (125)I-labelled congeners.
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spelling pubmed-53041642017-03-14 Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA Pereira, Edgar do Quental, Letícia Palma, Elisa Oliveira, Maria Cristina Mendes, Filipa Raposinho, Paula Correia, Isabel Lavrado, João Di Maria, Salvatore Belchior, Ana Vaz, Pedro Santos, Isabel Paulo, António Sci Rep Article A new family of (99m)Tc(I)- tricarbonyl complexes and (125)I-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 and (127)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 ((99m)Tc or (125)I) 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, (125)I-C(5) and (99m)Tc-C(3), 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 (99m)Tc can induce DNA damage with similar efficiency to that of (125)I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of (99m)Tc-C(3) in tumoral cells suggests that (99m)Tc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the (125)I-labelled congeners. Nature Publishing Group 2017-02-13 /pmc/articles/PMC5304164/ /pubmed/28211920 http://dx.doi.org/10.1038/srep42544 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Pereira, Edgar
do Quental, Letícia
Palma, Elisa
Oliveira, Maria Cristina
Mendes, Filipa
Raposinho, Paula
Correia, Isabel
Lavrado, João
Di Maria, Salvatore
Belchior, Ana
Vaz, Pedro
Santos, Isabel
Paulo, António
Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title_full Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title_fullStr Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title_full_unstemmed Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title_short Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
title_sort evaluation of acridine orange derivatives as dna-targeted radiopharmaceuticals for auger therapy: influence of the radionuclide and distance to dna
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304164/
https://www.ncbi.nlm.nih.gov/pubmed/28211920
http://dx.doi.org/10.1038/srep42544
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