Title: Long-Term Toxicity of 213Bi-Labelled BSA in Mice
Authors: DORSO LaetitiaBIGOT-CORBEL EdithABADIE JeromeDIAB MayaGOUARD S.BRUCHERTSEIFER FrankMORGENSTERN AlfredMAUREL CCHEREL M.DAVODEAU F
Citation: PLOS ONE vol. 11 no. 3 p. e0151330
Publisher: PUBLIC LIBRARY SCIENCE
Publication Year: 2016
JRC N°: JRC90199
ISSN: 1932-6203
URI: http://publications.jrc.ec.europa.eu/repository/handle/JRC90199
DOI: 10.1371/journal.pone.0151330
Type: Articles in periodicals and books
Abstract: BACKGROUND: Short-term toxicological evaluations have been reported for alpha-radioimmunotherapy (RIT) preclinical assays, particularly using bismuth-213 (213Bi). Toxicity is greatly influenced by the pharmacokinetics and binding specificity of the vector. It is difficult to assess the effect of non-specific irradiation due to the presence and persistence of the circulating radiopharmaceutical in the blood. To assess this we performed an acute and chronic toxicity study in mice injected with 213Bi-labeled Bovine Serum Albumin (BSA) as a paragon of a long-term circulating vector. METHOD: Biodistribution kinetics of BSA and of two non-specific antibodies were evaluated after intravascular administration and the organ absorbed dose for each vector labeled with 213Bi was calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of 213Bi-BSA and were followed-up for 385 days. Biochemical 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. Histological examination of mouse organs was performed at different time points in the follow-up period. RESULTS: Hematological toxicity was transient and non-limiting for all evaluated activities since at the highest injected activity (11.1MBq) mice died with liver and kidney failure but a normal blood cell count (median survival time of 189 days). This liver toxicity was objectified by an increase of both ALT and AST and by histological examination. Mice injected with 7.4 MBq of 213Bi-BSA had a median survival time of 324 days with increased plasma BUN and creatinine, due to impaired kidney function that was confirmed by histological examination. Injection of 3.7MBq 213Bi-BSA was safe, with no obvious plasma enzyme modifications nor significant histological abnormalities. CONCLUSION: Hematological toxicity was not a limiting feature in this study. Hepatic injury leading to liver failure was observed at the highest injected dose which is consistent with liver damage observed in human clinical trials. For the intermediate injected activity, the benefit-risk balance should be evaluated because of the risk of long-term toxicity to kidney.
JRC Directorate:Nuclear Safety and Security

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