Am/Cm(III) and DTPA/LIHOPO interactions with renal cells in vitro studied by bioassays, luminescence spectroscopy, and microdosimetry

Incorporation of trivalent actinide ions into the human body holds inherent significant chemo- and radiotoxic risks. This necessitates effective decorporation strategies based on knowledge of the underlying mechanisms of molecular and cellular actinide interactions. For americium and curium (Am/Cm), that state of knowledge is low. Therefore, this study represents the first comprehensive investigation on the impact of ²⁴³Am and the decorporation agents CaNa₃-DTPA (DTPA) and 3,4,3-LI(1,2-HOPO) (LIHOPO) on rat kidney cells. Following in vitro exposition experiments, the analyses included various cell-based bioassays complemented by microdosimetric calculations, cellular uptake measurements, and Am/Cm speciation studies. Results demonstrate that cell viability and morphology are severely impaired and cell death processes, oxidative stress, and DNA double strand breaks are induced in a time- and concentration-dependent manner after Am exposure. Furthermore, α-particle radiation from extracellular Am in the cell culture medium is the main contributor to radiation dose. There is evidence that ROS and caspase 3/7 induction are most likely related to Am chemotoxicity, whereas DNA double strand breaks mainly depend on extracellular Am radiotoxicity. DTPA leads to the formation of largely cell impermeable AmDTPA^2- significantly reducing intracellular metal uptake and cytotoxicity. In contrast, LIHOPO forms highly cell permeable AmLIHOPO^- enhancing intracellular metal uptake and cytotoxicity under steady-state conditions. This study provides useful insights for radiation protection against Am/Cm and may help to explain observations in clinical trials with new potential decorporation agents.