Direct and Auger Electron-Induced, Single- and Double-Strand Breaks on Plasmid DNA Caused by Tc-99m-Labeled Pyrene Derivatives and the Effect of Bonding Distance

作者：Reissig Falco^*; Mamat Constantin; Steinbach Joerg; Pietzsch Hans Juergen; Freudenberg Robert; Navarro Retamal Carlos; Caballero Julio; Kotzerke Joerg; Wunderlich Gerd^*

来源：PLos One, 2016, 11(9): e0161973.

DOI：10.1371/journal.pone.0161973

It is evident that Tc-99m causes radical-mediated DNA damage due to Auger electrons, which were emitted simultaneously with the known gamma-emission of Tc-99m. We have synthesized a series of new Tc-99m-labeled pyrene derivatives with varied distances between the pyrene moiety and the radionuclide. The pyrene motif is a common DNA intercalator and allowed us to test the influence of the radionuclide distance on damages of the DNA helix. In general, pUC 19 plasmid DNA enables the investigation of the unprotected interactions between the radiotracers and DNA that results in single-strand breaks (SSB) or double-strand breaks (DSB). The resulting DNA fragments were separated by gel electrophoresis and quantified by fluorescent staining. Direct DNA damage and radical-induced indirect DNA damage by radiolysis products of water were evaluated in the presence or absence of the radical scavenger DMSO. We demonstrated that Auger electrons directly induced both SSB and DSB in high efficiency when Tc-99m was tightly bound to the plasmid DNA and this damage could not be completely prevented by DMSO, a free radical scavenger. For the first time, we were able to minimize this effect by increasing the carbon chain lengths between the pyrene moiety and the Tc-99m nuclide. However, a critical distance between the Tc-99m atom and the DNA helix could not be determined due to the significantly lowered DSB generation resulting from the interaction which is dependent on the type of the Tc-99m binding motif. The effect of variable DNA damage caused by the different chain length between the pyrene residue and the Tc-core as well as the possible conformations of the applied Tc-complexes was supplemented with molecular dynamics (MD) calculations. The effectiveness of the DNA-binding Tc-99m-labeled pyrene derivatives was demonstrated by comparison to non-DNA- binding (TcO4-)-Tc-99m, since nearly all DNA damage caused by (TcO4-)-Tc-99m was prevented by incubating with DMSO.

• 出版日期2016-9-1
• 单位上海生物信息技术研究中心