Evaluation of Ce as a PET imaging surrogate for antibody drug conjugates incorporating Ac.

Nucl Med Biol

Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; Department of Nuclear Engineering, University of California, Berkeley, CA, USA. Electronic address:

Published: June 2022

Introduction: The in vivo generator Ce/La has the potential to serve as a PET imaging surrogate for both alpha-emitting Ac and Th radionuclides due to the unique Ce/Ce redox couple and the relatively long half-life of Ce. The purpose of this study was to demonstrate the compatibility of Ce with DOTA-based antibody drug conjugates, which would act as therapeutic agents when incorporating Ac.

Methods: The in vivo biodistributions of [Ce]Ce-DOTA and [Ce]Ce-citrate were assayed by microPET imaging over 25 h in Swiss Webster mice to determine the in vivo stability of the [Ce]Ce-DOTA complex. L-edge X-ray absorption spectroscopy measurements were used to confirm the Ce oxidation state and the formation of a fully coordinated Ce-DOTA complex. The in vivo biodistribution of [Ce]Ce-DOTA-Trastuzumab was assayed over 147 h by microPET imaging in SK-OV-3 tumor-bearing NOD SCID mice to evaluate tumor uptake and in vivo stability. Mice were euthanized at 214 h after administration of the radiolabeled antibody conjugate, and imaged 1 h later. An ex vivo biodistribution experiment was then performed in order to corroborate the PET images.

Results: [Ce]Ce-DOTA displayed rapid renal elimination and high in vivo stability over 25 h, with negligible bone and liver uptake, in comparison to [Ce]Ce-citrate. L-edge X-ray absorption spectroscopy experiments confirmed the 3+ oxidation state within the stable Ce-DOTA complex. MicroPET images of [Ce]Ce-DOTA-Trastuzumab displayed elevated tumor uptake over 214 h, with minimal bone and liver uptake analogous to previously reported [Ac]Ac-DOTA-Trastuzumab biodistribution results, and the ex vivo biodistribution of [Ce]Ce-DOTA-Trastuzumab corroborated the final PET images.

Conclusion: These results demonstrate that Ce allows for long-term tumor targeting with DOTA-based antibody drug conjugates and may therefore be used to trace antibody drug conjugates incorporating Ac.

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Source
http://dx.doi.org/10.1016/j.nucmedbio.2022.04.007DOI Listing

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