Lahrouch Florian, Chamayou Anne Christine, Creff Gaëlle, Duvail Magali, Hennig Christoph, Lozano Rodriguez Marisol Janeth, Den Auwer Christophe, Di Giorgio Christophe
Institut de Chimie de Nice, Université Côte d'Azur, CNRS , 06108 Nice, France.
Institut de Chimie Séparative de Marcoule, UMR 5257, CEA-CNRS-Université Montpellier-ENSCM , Site de Marcoule, BP 17171, 30207 Bagnols-sur-Cèze, France.
Inorg Chem. 2017 Feb 6;56(3):1300-1308. doi: 10.1021/acs.inorgchem.6b02408. Epub 2017 Jan 17.
Natural uranium has a very limited radioactive dose impact, but its chemical toxicity due to chronic exposure is still a matter of debate. Once inside the human body, the soluble uranium, under its uranyl form (U(VI)), is quickly removed from the blood system, partially excreted from the body, and partially retained in targeted organs, that is, the kidneys and bone matrix essentially. It is then crucial to remove or prevent the incorporation of uranium in these organs to limit the long-term chronic exposure. A lot of small chelating agents such as aminocarboxylates, catecholamides, and hydroxypyridonates have been developed so far. However, they suffer from poor selectivity and targeting abilities. Macromolecules and polymers are known to present a passive accumulation (size related), that is, the so-called enhanced permeability and retention effect, toward the main organs, which can be used as indirect targeting. Very interestingly, the methyl carboxylated polyethylenimine (PEI-MC) derivative has been described as a potent sequestering agent for heavy metals. It would be therefore an interesting candidate to evaluate as a new class of decorporation agents with passive targeting capabilities matching uranium preferential sequestering sites. In the present work, we explored the ability of a highly functionalized (89% rate) PEI-MC to uptake U(VI) close to physiological pH using a combination of analytical and spectroscopic techniques (inductively coupled plasma optical emission spectrometry (ICP-OES); extended X-ray absorption fine structure (EXAFS); and Fourier transformed infrared (FT-IR)) together with molecular dynamics (MD) simulation. A maximum loading of 0.47 mg U(VI) per milligram of PEI-MC was determined by ICP-OES measurements. From FT-IR data, a majority of monodentate coordination of the carboxylate functions of the PEI-MC seems to occur. From EXAFS and MD, a mix of mono and bidentate coordination mode was observed. Note that agreement between the EXAFS metrical parameters and MD radial distribution functions is remarkable. To the best of our knowledge, this is the first comprehensive structural study of a macromolecular PEI-based agent considered for uranium decorporation purposes.
天然铀的放射性剂量影响非常有限，但其因长期接触而产生的化学毒性仍是一个有争议的问题。一旦进入人体，可溶态铀以铀酰形式（U(VI)）存在，会迅速从血液系统中清除，部分排出体外，部分保留在靶器官中，主要是肾脏和骨基质。因此，去除或防止铀在这些器官中的蓄积对于限制长期慢性暴露至关重要。到目前为止，已经开发了许多小分子螯合剂，如氨基羧酸盐、儿茶酚胺和羟基吡啶酮酸盐。然而，它们的选择性和靶向能力较差。已知大分子和聚合物对主要器官具有被动蓄积作用（与尺寸有关），即所谓的增强渗透和滞留效应，可用于间接靶向。非常有趣的是，甲基羧化聚乙烯亚胺（PEI-MC）衍生物已被描述为一种有效的重金属螯合剂。因此，它作为一类具有与铀优先螯合位点相匹配的被动靶向能力的新型促排剂进行评估将是一个有趣的候选物。在本工作中，我们使用分析和光谱技术（电感耦合等离子体发射光谱法（ICP-OES）、扩展X射线吸收精细结构（EXAFS）和傅里叶变换红外光谱（FT-IR））以及分子动力学（MD）模拟相结合的方法，研究了一种高功能化（89%比例）的PEI-MC在接近生理pH值时摄取U(VI)的能力。通过ICP-OES测量确定每毫克PEI-MC对U(VI)的最大负载量为0.47毫克。根据FT-IR数据，PEI-MC的羧酸盐官能团似乎大多以单齿配位形式存在。从EXAFS和MD结果来看，观察到了单齿和双齿配位模式的混合。需要注意的是，EXAFS测量参数与MD径向分布函数之间的一致性非常显著。据我们所知，这是首次对一种用于铀促排目的的基于PEI的大分子试剂进行全面的结构研究。
