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

Pavel Lobachevsky, George R. Clark, Patrycja D. Pytel, Brenda Leung, Colin Skene, Laura Andrau, Jonathan M. White, Tom Karagiannis, Carleen Cullinane, Boon Q. Lee, Andrew Stuchbery, Tibor Kibedi, Rodney J. Hicks, Roger F. Martin

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3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)686-697
Number of pages12
JournalInternational Journal of Radiation Biology
Volume92
Issue number11
DOIs
Publication statusPublished - Nov 2016
Externally publishedYes

Keywords

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

Cite this

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. / Strand breakage by decay of DNA-bound 124I provides a basis for combined PET imaging and Auger endoradiotherapy. In: International Journal of Radiation Biology. 2016 ; Vol. 92, No. 11. pp. 686-697.
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title = "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 electrons, Auger emitters, Auger endoradiotherapy, DNA double-strand breaks, iodine-124, Monte Carlo simulation",
author = "Pavel Lobachevsky and Clark, {George R.} and Pytel, {Patrycja D.} and Brenda Leung and Colin Skene and Laura Andrau and White, {Jonathan M.} and Tom Karagiannis and Carleen Cullinane and Lee, {Boon Q.} and Andrew Stuchbery and Tibor Kibedi and Hicks, {Rodney J.} and Martin, {Roger F.}",
year = "2016",
month = "11",
doi = "10.3109/09553002.2015.1136852",
language = "English",
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journal = "International Journal of Radiation Biology",
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Lobachevsky, P, Clark, GR, Pytel, PD, Leung, B, Skene, C, Andrau, L, White, JM, Karagiannis, T, Cullinane, C, Lee, BQ, Stuchbery, A, Kibedi, T, Hicks, RJ & Martin, RF 2016, 'Strand breakage by decay of DNA-bound 124I provides a basis for combined PET imaging and Auger endoradiotherapy', International Journal of Radiation Biology, vol. 92, no. 11, pp. 686-697. https://doi.org/10.3109/09553002.2015.1136852

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

In: International Journal of Radiation Biology, Vol. 92, No. 11, 11.2016, p. 686-697.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Strand breakage by decay of DNA-bound 124I provides a basis for combined PET imaging and Auger endoradiotherapy

AU - Lobachevsky, Pavel

AU - Clark, George R.

AU - Pytel, Patrycja D.

AU - Leung, Brenda

AU - Skene, Colin

AU - Andrau, Laura

AU - White, Jonathan M.

AU - Karagiannis, Tom

AU - Cullinane, Carleen

AU - Lee, Boon Q.

AU - Stuchbery, Andrew

AU - Kibedi, Tibor

AU - Hicks, Rodney J.

AU - Martin, Roger F.

PY - 2016/11

Y1 - 2016/11

N2 - 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.

AB - 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.

KW - Auger electrons

KW - Auger emitters

KW - Auger endoradiotherapy

KW - DNA double-strand breaks

KW - iodine-124

KW - Monte Carlo simulation

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DO - 10.3109/09553002.2015.1136852

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JO - International Journal of Radiation Biology

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