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

PLoS One. 2016 Mar 16;11(3):e0151330. doi: 10.1371/journal.pone.0151330. eCollection 2016.

Abstract

Background: Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 (213Bi). 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 213Bi-labelled Bovine Serum Albumin (213Bi-BSA) as an example of a long-term circulating vector.

Method: Biodistribution of 213Bi-BSA and 125I-BSA were compared in order to evaluate 213Bi uptake by healthy organs. The doses to organs for injected 213Bi-BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of 213Bi-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 213Bi-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 213Bi-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bismuth / chemistry
  • Bismuth / pharmacokinetics
  • Bismuth / toxicity*
  • Cattle
  • Female
  • Mice
  • Mice, Nude
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / pharmacokinetics
  • Serum Albumin, Bovine / toxicity*
  • Tissue Distribution

Substances

  • Serum Albumin, Bovine
  • Bismuth

Grants and funding

This work was supported by the Labex IRON project (n° ANR-11-LABX-0018-01), and the ArronaxPlus Equipex project (n◦ ANR-11-EQPX-0004) funded by the «Investissements d'Avenir» French Government program, managed by the French National Research Agency (ANR). This work was also supported by the region «Pays de la Loire»: NUCSAN project (n° 2010 10255 ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.