Strand breakage by decay of DNA-bound ¹²⁴I provides a basis for combined PET imaging and Auger endoradiotherapy

Abstract

Purpose DNA ligands labelled with ¹²⁵I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of ¹²⁵I is suboptimal for therapy, we have investigated another Auger-emitter ¹²⁴I, with shorter half-life (4.18 days), and the additional feature of positron-emission, enabling positron emission tomography (PET) imaging. The purpose of this study was to compare the two radionuclides on the basis of DNA DSB per decay.

Materials and methods Using a ¹²⁴I- (or ¹²⁵I)-labelled minor groove binding DNA ligand, we investigated DNA breakage using the plasmid DNA assay. Biodistribution of the conjugate of the labelled ligand with transferrin was investigated in nude mice bearing a K562 human lymphoma xenograft.

Results The probability of DSB per decay was 0.58 and 0.85 for ¹²⁴I and ¹²⁵I, respectively, confirming the therapeutic potential of the former. The crystal structure of the ligand DNA complex shows the iodine atom deep within the minor groove, consistent with the high efficiency of induced damage. Biodistribution studies, including PET imaging, showed distinctive results for the conjugate, compared to the free ligand and transferrin, consistent with receptor-mediated delivery of the ligand.

Conclusions Conjugation of ¹²⁴I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.

Keywords:

• Auger emitters
• Auger electrons
• DNA double-strand breaks
• iodine-124
• Auger endoradiotherapy
• Monte Carlo simulation

Acknowledgements

The authors would like to thank Rachael Walker, Susan Jackson and Ekaterina Bogatyreva for technical assistance.

Disclosure statement

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Funding information

The project was supported by the grants from National Health and Medical Research Council (Project Grants 209125 and 350359) and by Cooperative Research Centre for Biological Imaging Development.