Novel Endoplasmic\nReticulum-Targeted Luminescent Probe\nfor Visualization of Carbon Monoxide in Drug-Induced Liver Injury

Drug-induced liver injury (DILI)\nis a major hepatic dysfunction\ncommonly caused by hepatotoxic drug overdose, resulting in a considerable\nnumber of fatalities worldwide. Recent studies have highlighted the\nregulatory and hepatoprotective effects of carbon monoxide (CO) during\nthe liver injury process. However, precisely tracking the dynamic\nchanges in the composition of CO in DILI is still a great challenge.\nIn this work, leveraging the innovative “quencher-insertion”\nstrategy, a unique endoplasmic reticulum (ER)-targetable lanthanide\ncomplex-based luminescence probe, <b>ER-ANBTTA-Eu</b><sup><b>3+</b></sup><b>/Tb</b><sup><b>3+</b></sup>, has been\ndeveloped for the selective and accurate monitoring of CO fluxes in\nlive cells and laboratory animals. The new probe is composed of three\ncovalently linked functional moieties: the terpyridine polyacid-Eu<sup>3+</sup>/Tb<sup>3+</sup>-mixed chelates as the long-lived luminophore,\na <i>p</i>-toluenesulfonamide moiety as the ER-anchoring\nmotif, and an allyloxy-nitrobenzyl ether moiety as the CO-specific\nrecognition unit. Upon reaction with CO in the presence of Pd<sup>2+</sup> ions, the Tsuji–Trost reaction leads to the cleavage\nof the allyloxy-nitrobenzyl group from the Eu<sup>3+</sup>/Tb<sup>3+</sup>-mixed chelates, which results in the restoration of Tb<sup>3+</sup> emission at 538 nm and the attenuation of Eu<sup>3+</sup> emission at 688 nm, leading to a dramatic increase of the <i>I</i><sub>538</sub>/<i>I</i><sub>688</sub> ratio.\nIn addition to the exceptional response sensitivity and selectivity\ntoward CO, <b>ER-ANBTTA-Eu</b><sup><b>3+</b></sup><b>/Tb</b><sup><b>3+</b></sup> also exhibits the outstanding\nER-locating capability, which allows the probe to be used for imaging\nof CO in the ER of live cells. Using this probe, combined with the\ntime-gated luminescence imaging mode, the exogenous and endogenous\nCO in ER of live cells were monitored without the interference of\nbackground autofluorescence. Moreover, the upregulation of hepatic\nCO in DILI mice was successfully visualized. The results suggested\nthe potential of <b>ER-ANBTTA-Eu</b><sup><b>3+</b></sup><b>/Tb</b><sup><b>3+</b></sup> for deeply exploring the\nfunctions of CO in DILI pathogenesis.