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Open AccessArticle

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

1
School of Biomedical Engineering and Imaging Sciences, King’s College London, Fourth Floor Lambeth Wing, St Thomas’ Hospital, London SE1 7EH, UK
2
Department of Chemistry, Hunter College, City University of New York, New York, NY 10021, USA
3
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(4), 1496; https://doi.org/10.3390/ijms21041496
Received: 30 December 2019 / Revised: 17 February 2020 / Accepted: 18 February 2020 / Published: 22 February 2020
(This article belongs to the Special Issue Advances on Chelation in Medicine)
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 68Ga 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 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ 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” 68Ga3+ 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 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. View Full-Text
Keywords: metal chelation; radionuclide imaging; pretargeting; gallium-68; hydroxypyridinones; monoclonal antibodies; bifunctional chelators metal chelation; radionuclide imaging; pretargeting; gallium-68; hydroxypyridinones; monoclonal antibodies; bifunctional chelators
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Imberti, C.; Adumeau, P.; Blower, J.E.; Al Salemee, F.; Baguña Torres, J.; Lewis, J.S.; Zeglis, B.M.; Terry, S.Y.A.; Blower, P.J. Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance. Int. J. Mol. Sci. 2020, 21, 1496.

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