Open AccessLong-Term Toxicity of 213Bi-Labelled BSA in Mice
Author(s) -
Laëtitia Dorso,
Édith Bigot-Corbel,
Jérôme Abadie,
Maya Diab,
Sébastien Gouard,
Frank Bruchertseifer,
Alfred Morgenstern,
Catherine Maurel,
Michel Chérel,
François Davodeau
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0151330
Subject(s) - toxicity , blood urea nitrogen , creatinine , medicine , biodistribution , pharmacokinetics , kidney , white blood cell , pharmacology , pathology , chemistry , in vitro , biochemistry
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.