Strand breakage by decay of DNA-bound 124I provides a basis for combined PET imaging and Auger endoradiotherapy. (1st November 2016)

• Record Type: Journal Article
• Authors: Lobachevsky, Pavel; Clark, George R.; Pytel, Patrycja D.; Leung, Brenda; Skene, Colin; Andrau, Laura; White, Jonathan M.; Karagiannis, Tom; Cullinane, Carleen; Lee, Boon Q.; Stuchbery, Andrew; Kibedi, Tibor; Hicks, Rodney J.; Martin, Roger F.
• Is Part Of: International journal of radiation biology. Volume 92:Number 11(2016:Nov.)
• Page Start: 686
• Page End: 697
• Publication Date: 2016-11-01
• Subjects: Auger emitters -- Auger electrons -- DNA double-strand breaks -- iodine-124 -- Auger endoradiotherapy -- Monte Carlo simulation; Radiation -- Physiological effect -- Periodicals; Radiobiology -- Periodicals; 571.45
• DOI: 10.3109/09553002.2015.1136852
• Languages: English
• ISSNs: 0955-3002

Abstract

Abstract: Purpose DNA ligands labelled with 125 I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of 125 I is suboptimal for therapy, we have investigated another Auger-emitter 124 I, 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 124 I- (or 125 I)-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 124 I and 125 I, 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 124 I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.