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

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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.


Chemical structures of the newly synthesized AO derivatives.
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f2: Chemical structures of the newly synthesized AO derivatives.

Mentions: Structurally related 99mTc- and 125I-labelled AO derivatives were designed sharing the same AO moiety and the same aminoalkyl spacers (Fig. 2). Thus, aminoalkyl-3,6-bis(dimethylamino)acridinium iodide precursors (8–10), containing three (C3), five (C5) and eight (C8) methylene units, were used as starting materials to obtain both classes of compounds (Supplementary Figs S1 and S3). These acridinium precursors were synthesized following previously described procedures21.


Evaluation of Acridine Orange Derivatives as DNA-Targeted Radiopharmaceuticals for Auger Therapy: Influence of the Radionuclide and Distance to DNA
Chemical structures of the newly synthesized AO derivatives.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Chemical structures of the newly synthesized AO derivatives.
Mentions: Structurally related 99mTc- and 125I-labelled AO derivatives were designed sharing the same AO moiety and the same aminoalkyl spacers (Fig. 2). Thus, aminoalkyl-3,6-bis(dimethylamino)acridinium iodide precursors (8–10), containing three (C3), five (C5) and eight (C8) methylene units, were used as starting materials to obtain both classes of compounds (Supplementary Figs S1 and S3). These acridinium precursors were synthesized following previously described procedures21.

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.