ArticleEuropean journal of nuclear medicine and molecular imaging2015
PET imaging of DNA damage using (89)Zr-labelled anti-γH2AX-TAT immunoconjugates.
Article in European journal of nuclear medicine and molecular imaging, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
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- CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody.Pharmaceuticals (Basel, Switzerland) · 2021Article
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- PET Imaging of PARP Expression UsingJournal of nuclear medicine : official publication, Society of Nuclear Medicine · 2019Article
- Avenues to molecular imaging of dying cells: Focus on cancer.Medicinal research reviews · 2018Review
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- Imaging the DNA damage response with PET and SPECT.European journal of nuclear medicine and molecular imaging · 2017Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeThe efficacy of most anticancer treatments, including radiotherapy, depends on an ability to cause DNA double-strand breaks (DSBs). Very early during the DNA damage signalling process, the histone isoform H2AX is phosphorylated to form γH2AX. With the aim of positron emission tomography (PET) imaging of DSBs, we synthesized a (89)Zr-labelled anti-γH2AX antibody, modified with the cell-penetrating peptide, TAT, which includes a nuclear localization sequence.
methods(89)Zr-anti-γH2AX-TAT was synthesized using EDC/NHS chemistry for TAT peptide linkage. Desferrioxamine conjugation allowed labelling with (89)Zr. Uptake and retention of (89)Zr-anti-γH2AX-TAT was evaluated in the breast adenocarcinoma cell line MDA-MB-468 in vitro or as xenografts in athymic mice. External beam irradiation was used to induce DSBs and expression of γH2AX. Since (89)Zr emits ionizing radiation, detailed radiobiological measurements were included to ensure (89)Zr-anti-γH2AX-TAT itself does not cause any additional DSBs.
resultsUptake of (89)Zr-anti-γH2AX-TAT was similar to previous results using (111)In-anti-γH2AX-TAT. Retention of (89)Zr-anti-γH2AX-TAT was eightfold higher at 1 h post irradiation, in cells expressing γH2AX, compared to non-irradiated cells or to non-specific IgG control. PET imaging of mice showed higher uptake of (89)Zr-anti-γH2AX-TAT in irradiated xenografts, compared to non-irradiated or non-specific controls (12.1 ± 1.6 vs 5.2 ± 1.9 and 5.1 ± 0.8%ID/g, respectively; p < 0.0001). The mean absorbed dose to the nucleus of cells taking up (89)Zr-anti-γH2AX-TAT was twofold lower compared to (111)In-anti-γH2AX-TAT. Additional exposure of neither irradiated nor non-irradiated cells nor tissues to (89)Zr-anti-γH2AX-TAT resulted in any significant changes in the number of observable DNA DSBs, γH2AX foci or clonogenic survival.
conclusion(89)Zr-anti-γH2AX-TAT allows PET imaging of DNA DSBs in a tumour xenograft mouse model.
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