Dual radionuclide theranostic pretargeting Journal Article


Authors: Keinänen, O.; Brennan, J. M.; Membreno, R.; Fung, K.; Gangangari, K.; Dayts, E. J.; Williams, C. J.; Zeglis, B. M.
Article Title: Dual radionuclide theranostic pretargeting
Abstract: Recent years have played witness to the advent of nuclear theranostics: the synergistic use of "matched pair" radiopharmaceuticals for diagnostic imaging and targeted radiotherapy. In this investigation, we report the extension of this concept to in vivo pretargeting based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO). We demonstrate that a single injection of a TCO-modified immunoconjugate can be used as a platform for pretargeted PET imaging and radiotherapy via the sequential administration of a pair of Tz-bearing radioligands labeled with the positron-emitting radiometal copper-64 (t1/2 ≈ 12.7 h) and the beta-emitting radiometal lutetium-177 (t1/2 ≈ 6.7 days). More specifically, a mouse model of human colorectal carcinoma received a dose of the A33 antigen-targeting immunoconjugate huA33-TCO, followed 24 and 48 h later by injections of [64Cu]Cu-SarAr-Tz and [177Lu]Lu-DOTA-PEG7-Tz, respectively. This approach produces high activity concentrations of both radioligands in tumor tissue (16.4 ± 2.7 %ID/g for [64Cu]Cu-SarAr-Tz at 48 h post-injection and 18.1 ± 2.1 %ID/g for [177Lu]Lu-DOTA-PEG7-Tz at 120 h post-injection) as well as promising tumor-to-healthy organ activity concentration ratios. Ultimately, we believe that this work could not only have important implications in nuclear theranostics-most excitingly with isotopologue-based radioligand pairs such as [64Cu]Cu-SarAr-Tz and [67Cu]Cu-SarAr-Tz-but also in the delivery of fractionated doses during pretargeted radioimmunotherapy. Copyright © 2019 American Chemical Society.
Keywords: positron emission tomography; colorectal cancer; pet; click chemistry; theranostics; a33 antigen; hua33; pretargeted radioimmunotherapy; pretargeting; tetrazine; bioorthogonal chemistry; multistep targeting; trans-cyclooctene; inverse electron demand diels-alder reaction
Journal Title: Molecular Pharmaceutics
Volume: 16
Issue: 10
ISSN: 1543-8384
Publisher: American Chemical Society  
Date Published: 2019-10-07
Start Page: 4416
End Page: 4421
Language: English
DOI: 10.1021/acs.molpharmaceut.9b00746
PUBMED: 31483993
PROVIDER: scopus
PMCID: PMC7169955
DOI/URL:
Notes: Source: Scopus
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  1. Brian Zeglis
    88 Zeglis