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High-sensitivity ICP-MS is a valid method for the preclinical characterization of metal-conjugates to be developed as future radiopharmaceuticals

Wallimann, Rahel, Schindler, Patrick, Hensinger, Heloise, Kneuer, Rainer, Tschan, Viviane, Busslinger, Sarah, Müller, Cristina and Schibli, Roger (2023) High-sensitivity ICP-MS is a valid method for the preclinical characterization of metal-conjugates to be developed as future radiopharmaceuticals. Molecular pharmaceutics, 20 (4). pp. 2150-2158. ISSN 1543-8384


The preclinical characterization of radiopharmaceuticals requires specialized laboratories to enable the manipulation of open radioactive sources and is associated with a dose burden to personnel. The aim of the study was, therefore, to investigate the in vitro and in vivo predictivity of inductively coupled plasma mass spectrometry (ICP-MS) of non-radioactive analogous metal-conjugates for the development of future radiopharmaceuticals. For proof-of-concept, [175Lu]Lu-/[177Lu]Lu-PSMA-617 and [159Tb]Tb-/[161Tb]Tb-PSMA-617 have been employed. Sample preparation procedures for the quantification of minute amounts of lutetium-175 and terbium-159 in cell and organ samples of in vitro and in vivo experiments by ICP-MS were developed and validated for their robustness and accuracy. Quantification limits for the investigated lanthanides by ICP-MS were identified at concentrations in the range of parts per quadrillion (ppq) to parts per trillion (ppt), recovery of the lanthanides after sample preparation was 98%, and matrix effect was reduced so that it was negligible (<1% in cell digests and <5% in organ digests). ICP-MS technology and conventional γ-counting technique provided highly similar results with an absolute <5% difference regarding the total uptake and the internalization for the Lu-PSMA-617 and the Tb-PSMA-617 in PSMA-positive tumor cells, respectively. In vivo, equal results for both methods using Lu- and Tb-labeled PSMA-617 were obtained. Most prominent was the uptake in PSMA-positive PC-3 PIP tumor xenografts for both, the Lu-PSMA-617 (48 ± 9 % ID/g, and 50 ± 9% IA/g, respectively, at 1 h p.i.) and Tb-PSMA-617 (44 ± 5 % ID/g, and 45 ± 5% IA/g, respectively, at 1 h p.i.). This study demonstrated that high-sensitivity ICP-MS, using stable metal isotopes, allows the reliable and predictive quantification of analogous radiometal-labeled conjugates in vitro and in vivo. Hence, ICP-MS can be employed as a valid alternative to state-of-the-art radioactive assays. This allows the development of novel radiopharmaceuticals in conventional research laboratories and supports radiopharmaceutical research in academia and industry.

Item Type: Article
Keywords: ICP-MS, γ-counting, metal-conjugates, radiopharmaceuticals, cancer research, PSMA-617
Date Deposited: 04 Jul 2023 00:45
Last Modified: 04 Jul 2023 00:45