Precise Monitoring of Drug-Induced Kidney Injury Using an Endoplasmic Reticulum-Targetable Ratiometric Time-Gated Luminescence Probe for Superoxide Anions

Drug-induced acute kidney injury (AKI), caused by renal drug metabolism, has been considered to be a major barrier in drug development and clinical treatment. Among various drugs, anticancer drugs, cisplatin, and aminoglycoside antibiotic gentamicin, are known to be able to induce excessive or unfolded accumulation of proteins in the endoplasmic reticulum (ER) of cells, leading to ER stress. Meanwhile, reactive oxygen species (ROS) are formed, and superoxide anion (O₂^•-), the first produced ROS, is a key species to induce the AKI. Due to the lack of appropriate tools, the early diagnosis of AKI induced by cisplatin, gentamicin, or other drugs is still a crucial challenge. Herein, we report a lanthanide complex-based ER-targetable luminescence probe for O₂^•-, ER-(4'-trifluoromethanesulfonyloxy-2,2':6',2''-terpyridine-6,6''-diyl)bis(methylenenitrilo)tetrakis (aceticacid) (NFTTA)-Eu³⁺/Tb³⁺, for the sensitive monitoring of drug-induced AKI via mapping the generation of O₂^•- in live cells and laboratory animals. Using this probe coupled with the ratiometric time-gated luminescence (RTGL) imaging technique, the changes of O₂^•- level in the ER of live cells induced by different stimuli were precisely monitored. More importantly, the substantial increases in O₂^•- levels were observed in the cisplatin- and gentamicin-induced kidney injury of mice. In addition, the protective effects of l-carnitine (LC) and epigallocatechin-3-gallate (EGCG) against cisplatin- and gentamicin-induced nephrotoxicity were visualized and elucidated for the first time. The results demonstrated the potential of ER-NFTTA-Eu³⁺/Tb³⁺ for examining and monitoring O₂^•- in drug-induced AKI and for providing a diagnosis and treatment of nephrotoxicity diseases.