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C.I. acknowledges the NIHR Biomedical Research Centre for a PhD studentship. This study was supported in part by the Geoffrey Beene Cancer Research Center of MSKCC (JSL), NIH NCI R35 CA232130 (JSL), and NIH U01CA221046 (JSL, BMZ), by the Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC WT088641/Z/09/Z, the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England), and by the NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London. The authors acknowledge the MSKCC Small Animal Imaging Core Facility, the Radiochemistry and Molecular Imaging Probe Core, which were supported by NIH, grant P30 CA08748. We gratefully acknowledge William H. and Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the DoH.

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Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance

Publicado en:INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 21 (4): 1496- - 2020-02-01 21(4), DOI: 10.3390/ijms21041496

Autores: Imberti, Cinzia; Adumeau, Pierre; Blower, Julia E; Al Salemee, Fahad; Torres, Julia Baguna; Lewis, Jason S; Zeglis, Brian M; Terry, Samantha Y A; Blower, Philip J

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Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind Ga-68 in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 mu g of THPMe-NCS-huA33, followed after 24 h by 8-10 MBq of Ga-68(3+)) with both a directly labelled radioimmunoconjugate (Zr-89-DFO-NCS-huA33, 88 mu g, 7 MBq) and a Ga-68-only negative control (8-10 MBq of Ga-68(3+)). Imaging was performed 25 h after antibody administration (1 h after Ga-68(3+) administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" Ga-68(3+) in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the Ga-68-only experiment was repeated using THPMe (20 mu g, 1 h after Ga-68(3+) administration) to clear circulating Ga-68(3+), producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a Ga-68 clearing agent in imaging applications with gallium citrate.

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