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

View Article: PubMed Central - PubMed

ABSTRACT

I-ctc-ctc-c: A new family of 99mTc(I)- tricarbonyl complexes and 125I-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 127I 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 or 125I) 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, 1255 and 99m3, 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 99mTc can induce DNA damage with similar efficiency to that of 125I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of 99m3 in tumoral cells suggests that 99mTc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the 125I-labelled congeners.

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Top view and all structure view of the molecular docking top-ranked poses of the AO derivatives intercalated in the d(ACGTACGT)2 sequence.(a) 125I-C3; (b) 125I-C5; (c) 125I-C8; (d) 99mTc-C3; (e) 99mTc-C5 and (f) 99mTc-C8. Distance between the 125I or 99mTc atom relative to the DNA helical axis is displayed in Å.
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f4: Top view and all structure view of the molecular docking top-ranked poses of the AO derivatives intercalated in the d(ACGTACGT)2 sequence.(a) 125I-C3; (b) 125I-C5; (c) 125I-C8; (d) 99mTc-C3; (e) 99mTc-C5 and (f) 99mTc-C8. Distance between the 125I or 99mTc atom relative to the DNA helical axis is displayed in Å.

Mentions: The molecular docking studies were performed with Molecular Operating Environment (MOE)28 and validated by first docking the bis-intercalating anthracycline drug present in the NMR solution structure (Supplementary Fig. S17). Using the same protocol, 125I-C3, 125I-C5, 125I-C8, 99mTc-C3, 99mTc-C5 and 99mTc-C8 were docked and the top-ranked positions are shown in Fig. 4.


Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
Top view and all structure view of the molecular docking top-ranked poses of the AO derivatives intercalated in the d(ACGTACGT)2 sequence.(a) 125I-C3; (b) 125I-C5; (c) 125I-C8; (d) 99mTc-C3; (e) 99mTc-C5 and (f) 99mTc-C8. Distance between the 125I or 99mTc atom relative to the DNA helical axis is displayed in Å.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5304164&req=5

f4: Top view and all structure view of the molecular docking top-ranked poses of the AO derivatives intercalated in the d(ACGTACGT)2 sequence.(a) 125I-C3; (b) 125I-C5; (c) 125I-C8; (d) 99mTc-C3; (e) 99mTc-C5 and (f) 99mTc-C8. Distance between the 125I or 99mTc atom relative to the DNA helical axis is displayed in Å.
Mentions: The molecular docking studies were performed with Molecular Operating Environment (MOE)28 and validated by first docking the bis-intercalating anthracycline drug present in the NMR solution structure (Supplementary Fig. S17). Using the same protocol, 125I-C3, 125I-C5, 125I-C8, 99mTc-C3, 99mTc-C5 and 99mTc-C8 were docked and the top-ranked positions are shown in Fig. 4.

View Article: PubMed Central - PubMed

ABSTRACT

I-ctc-ctc-c: A new family of 99mTc(I)- tricarbonyl complexes and 125I-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 127I 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 or 125I) 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, 1255 and 99m3, 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 99mTc can induce DNA damage with similar efficiency to that of 125I, when both are positioned at comparable distances to the double helix. Furthermore, the high nuclear retention of 99m3 in tumoral cells suggests that 99mTc-labelled AO derivatives are more promising for the design of Auger-emitting radiopharmaceuticals than the 125I-labelled congeners.

No MeSH data available.


Related in: MedlinePlus