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Developing the 134Ce and 134La pair as companion positron emission tomography diagnostic isotopes for 225Ac and 227Th radiotherapeutics

Nature Chemistry volume 13, pages 284–289 (2021)Cite this article

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Abstract

Developing targeted α-therapies has the potential to transform how diseases are treated. In these interventions, targeting vectors are labelled with α-emitting radioisotopes that deliver destructive radiation discretely to diseased cells while simultaneously sparing the surrounding healthy tissue. Widespread implementation requires advances in non-invasive imaging technologies that rapidly assay therapeutics. Towards this end, positron emission tomography (PET) imaging has emerged as one of the most informative diagnostic techniques. Unfortunately, many promising α-emitting isotopes such as 225Ac and 227Th are incompatible with PET imaging. Here we overcame this obstacle by developing large-scale (Ci-scale) production and purification methods for 134Ce. Subsequent radiolabelling and in vivo PET imaging experiments in a small animal model demonstrated that 134Ce (and its 134La daughter) could be used as a PET imaging candidate for 225AcIII (with reduced 134CeIII) or 227ThIV (with oxidized 134CeIV). Evaluating these data alongside X-ray absorption spectroscopy results demonstrated how success relied on rigorously controlling the CeIII/CeIV redox couple.

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Fig. 1: The two readily accessible oxidation states of cerium make it an ideal elemental analogue for the actinides, actinium and thorium.
Fig. 2: Control of 134Ce oxidation state enables purification of 134Ce from a natLa target.
Fig. 3: XAS spectroscopy enables monitoring of the cerium oxidation state throughout the purification and labelling processes.
Fig. 4: Coronal maximum intensity projection PET images of 134Ce complexes evidence different excretion pathways depending on the chelator and cerium oxidation state.
Fig. 5: Biodistribution of 134CeIV-3,4,3-LI(1,2-HOPO) and 134CeIII-DTPA in selected organs confirm conclusions drawn from PET imaging.

Data availability

All data and experimental details supporting the findings discussed here are available within the paper and its Supplementary Information.

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Acknowledgements

We thank M. Janabi for help with the μ-PET instrument and G.J.-P. Deblonde for discussions. This research was supported by the US Department of Energy (DOE) Isotope Program, managed by the Office of Science for Nuclear Physics (LBNL contract DE-AC02-05CH11231; LANL Contract 89233218CNA000001). LANL is an affirmative action/equal opportunity employer managed by Triad National Security, LLC, for the National Nuclear Security Administration of the US DOE. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, was supported by the DOE, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. We acknowledge additional support from a DOE Integrated University Program graduate research fellowship (K.M.S.) and a Nuclear Regulatory Commission Faculty Development Grant (NRC-HQ-84-14-G-0052; R.J.A.).

Dedication: We dedicate this work to the memory of our colleague and friend Dr. J. P. O’Neil.

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Author notes

  1. These authors contributed equally: Tyler A. Bailey, Veronika Mocko, Katherine M. Shield.

Authors and Affiliations

  1. Department of Nuclear Engineering, University of California, Berkeley, CA, USA

    Tyler A. Bailey, Katherine M. Shield & Rebecca J. Abergel

  2. Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Tyler A. Bailey, Katherine M. Shield, Dahlia D. An, Stacey S. Gauny, Andrew L. Lakes & Rebecca J. Abergel

  3. Los Alamos National Laboratory, Los Alamos, NM, USA

    Veronika Mocko, Andrew C. Akin, Eva R. Birnbaum, Mark Brugh, Jason C. Cooley, Michael E. Fassbender, Francois M. Nortier, Ellen M. O’Brien, Sara L. Thiemann, Frankie D. White, Christiaan Vermeulen & Stosh A. Kozimor

  4. Department of Medical Physics, University of Wisconsin, Madison, WI, USA

    Jonathan W. Engle

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Contributions

T.A.B., V.M., K.M.S., J.W.E., F.D.W., C.V., S.A.K. and R.J.A. conceived and designed the experiments. T.A.B., V.M., K.M.S., D.D.A., A.C.A., M.B., J.C.C., M.E.F, S.S.G., A.L.L., F.M.N., E.M.O., S.L.T., C.V. and S.A.K. performed the experiments. T.A.B., V.M., K.M.S., F.D.W., C.V., S.A.K. and R.J.A. analysed the data and co-wrote the paper. T.A.B., V.M. and K.M.S. contributed equally to this work. All authors discussed the results and commented on the manuscript.

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Correspondence to Christiaan Vermeulen, Stosh A. Kozimor or Rebecca J. Abergel.

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Supplementary Discussion, Figs. 1–2 and Tables 1–2.

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Bailey, T.A., Mocko, V., Shield, K.M. et al. Developing the 134Ce and 134La pair as companion positron emission tomography diagnostic isotopes for 225Ac and 227Th radiotherapeutics. Nat. Chem. 13, 284–289 (2021). https://doi.org/10.1038/s41557-020-00598-7

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