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Long-Term Toxicity of [213]Bi-Labelled BSA in Mice

Abstract : Background Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 ([213]Bi). Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with [213]Bi-labelled Bovine Serum Albumin ([213]Bi-BSA) as an example of a long-term circulating vector. Method Biodistribution of [213]Bi-BSA and [125]I-BSA were compared in order to evaluate [213]Bi uptake by healthy organs. The doses to organs for injected [213]Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of [213]Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells) were performed. Mouse organs were examined histologically at different time points. Results Haematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq), mice died from liver and kidney failure (median survival of 189 days). This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of [213]Bi-BSA (median survival of 324 days) had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of [213]Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities. Conclusion Haematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq), consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq) should be used with caution because of the risk of long-term toxicity to kidneys.
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Laetitia Dorso, Edith Bigot-Corbel, Jérôme Abadie, Maya Diab, Sebastien Gouard, et al.. Long-Term Toxicity of [213]Bi-Labelled BSA in Mice. PLoS ONE, Public Library of Science, 2016, 11 (3), ⟨10.1371/journal.pone.0151330⟩. ⟨inserm-01809417⟩

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