Laboratory of Radio Toxicology, CEA, Paris-Saclay University, 91297 Arpajon, France.
CEA, CNRS, BIAM, UMR7265, IPM, Aix Marseille Univ, 13108 Saint Paul-Lez-Durance, France.
Toxicol In Vitro. 2020 Aug;66:104863. doi: 10.1016/j.tiv.2020.104863. Epub 2020 Apr 15.
Inhalation of CoO particles may occur at the work place in nuclear industry. Their low solubility may result in chronic lung exposure to γ rays. Our strategy for an improved therapeutic approach is to enhance particle dissolution to facilitate cobalt excretion, as the dissolved fraction is rapidly eliminated, mainly in urine. In vitro dissolution of CoO particles was assessed with two complementary assays in lung fluid surrogates to mimic a pulmonary contamination scenario. Twenty-one molecules and eleven combinations were selected through an extensive search in the literature, based on dissolution studies of other metal oxides (Fe, Mn, Cu) and tested for dissolution enhancement of cobalt particles after 1-28 days of incubation. DTPA, the recommended treatment following cobalt contamination did not enhance CoO particles dissolution when used alone. However, by combining molecules with different properties, such as redox potential and chelating ability, we greatly improved the efficacy of each drug used alone, leading for the highest efficacy, to a 2.7 fold increased dissolution as compared to controls. These results suggest that destabilization of the particle surface is an important initiating event for a good efficacy of chelating drugs, and open new perspectives for the identification of new therapeutic strategies.
在核工业工作场所可能会吸入 CoO 颗粒。其低溶解度可能导致慢性肺部 γ 射线暴露。我们的治疗策略是增强颗粒的溶解，以促进钴的排泄，因为溶解部分主要在尿液中迅速消除。在体外，使用两种互补的肺液替代物测定来评估 CoO 颗粒的溶解，以模拟肺部污染情况。根据其他金属氧化物（Fe、Mn、Cu）的溶解研究，通过广泛的文献检索，选择了 21 种分子和 11 种组合，并在 1-28 天孵育后测试了它们对钴颗粒溶解的增强作用。DTPA 是钴污染后的推荐治疗药物，但单独使用时并不能增强 CoO 颗粒的溶解。然而，通过结合具有不同性质的分子，如氧化还原电位和螯合能力，我们大大提高了每种药物单独使用的疗效，使溶解度提高了 2.7 倍，与对照组相比。这些结果表明，颗粒表面的不稳定性是螯合药物疗效良好的一个重要起始事件，并为确定新的治疗策略开辟了新的前景。
