Speciation-dependent cellular uptake and cytotoxicity of tri- and tetravalent lanthanides and actinides in/onto mammalian kidney cells

拟议项目的总体目标是扩大和改进关于将三价和四价锕系元素和镧系元素转移到哺乳动物细胞中的知识。研究是在痕量浓度水平下进行的，每个浓度水平都有一个代表性的稳定的三价和四价锕系元素，即。e. Cm（III）/Am（III）和Pu（IV），以及Ce（III，IV）作为各自的镧系元素类似物。由于这些元素在最初的24小时内通过肾脏排泄，因此在拟议的项目中选择性地研究了哺乳动物的肾脏细胞。一个具体的目标是探索这些元素的细胞摄取，它们在细胞表面的积累和它们的细胞毒性。这些研究将根据元素的形态进行，即。例如，氧化态、金属离子浓度和抗衡离子，以及取决于孵育时间。对相关生物流体中所选元素的形态进行了理论模拟和实验研究。例如，人尿和不同的细胞培养基作为其支持基础。拟议项目的另一个方面是确定具有相同氧化态的4f和5 f元素的生物和生物化学行为的相似性和/或差异，从而检查生物化学领域中的锕系镧系元素类比。所提出的项目的结果将提供以前未知的热力学复杂的Pu，Cm/Am，和Ce与生物相关的配体的稳定常数。这些数据有助于扩大数据库，并促进更可靠的未来建模的三价和四价锕系元素和镧系元素在体液和细胞培养基中的形态。此外，将确定这些元素的细胞摄取、它们在细胞表面上的积累和暴露的肾细胞的活力率的数值。这些数据有助于更深入地了解参与细胞摄取和毒性的锕系元素和镧系元素的生化过程。在未来，这也可能有助于开发新的特定的去污程序和去污剂。

The general aim of the proposed project is to expand and improve the insufficient knowledge about the transfer of tri- and tetravalent actinides and lanthanides into mammalian cells. Investigations are performed at the trace concentration level each with one representative of stable tri- and tetravalent actinides, i. e. Cm(III)/Am(III) and Pu(IV), as well as Ce(III, IV) as the respective lanthanide analog. Due to the excretion of these elements via the kidneys during the first 24 hours, selectively mammalian kidneys cells are studied in the proposed project. One specific goal is to explore the cellular uptake of these elements, their accumulation on the cell surface and their cytotoxicity. These investigations will be performed in dependence on the speciation of an element, i. e., the oxidation state, metal ion concentration, and counter ion, as well as in dependence on the incubation time. Theoretical modeling and experimental studies on the speciation of the selected elements in a relevant biofluid, i. e., human urine, and different cell culture media serve as a supporting basis for this. Another aspect of the proposed project is to determine the similarities and/or differences of the biological and biochemical behavior of 4f and 5f elements with the same oxidation state and, thus, to check the actinide lanthanide analogy in the field of biochemistry. The results of the proposed project will provide previously unknown thermodynamic complex stability constants of Pu, Cm/Am, and Ce with biological relevant ligands. Theses data contribute to an expanded data base and facilitate more reliable future modeling of the speciation of tri- and tetravalent actinides and lanthanides in body fluids and cell culture media. Furthermore, numerical values for the cellular uptake of these elements, their accumulation on the cell surface and the rate of vitality for the exposed kidney cells will be determined. These data contribute to a more profound knowledge of the biochemical processes involved into the cellular uptake and toxicity of actinides and lanthanides. In future, this may also contribute to the development of new specific decontamination procedures and decorporation agents.