Exploring the PET in vivo generator 134 Ce as a theranostic match for 225 Ac
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Purpose
The radionuclide pair cerium-134/lanthanum-134 ( 134 Ce/ 134 La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 ( 225 Ac). The unique properties of 134 Ce offer perspectives for developing innovative in vivo investigations not possible with 225 Ac. In this work, 225 Ac- and 134 Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, 134 Ce/ 134 La has limitations to the setting of quantitative positron emission tomography imaging.
Methods
The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG 8 -Tz) were radiolabelled with 225 Ac or 134 Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The 225 Ac and 134 Ce-labeled mcp-PEG 8 -Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
Results
In vitro and in vivo studies with both 225 Ac and 134 Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134 Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134 Ce’s PET-compatible daughter 134 La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225 Ac-labelled tracers are not quantitatively represented by 134 Ce PET imaging.
Conclusion
When employing slow-internalizing vectors, 134 Ce might not be an ideal match for 225 Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134 La. However, this same characteristic makes it possible to estimate the redistribution of 225 Ac’s progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.
TOC Graphic
Redistribution of progeny. Investigating the 225 Ac and 134 Ce decay chain. This figure was created with BioRender.
