Novel cyclometalated iridium(III) complex-based two-photon probe for visualizing mitochondrial nitroreductase and assessing treatment responses in sepsis-induced lung injury.

Background: Sepsis-induced lung injury (SILI) is an acute condition characterized by respiratory failure, with lung hypoxia as a prominent feature. Nitroreductase (NTR) is significantly upregulated during SILI, highlighting its potential as a promising biomarker for assessing the severity of SILI and monitoring therapeutic response. Molecular biology studies indicate that mitochondria serve as potential therapeutic targets for SILI. Accurate monitoring of mitochondrial NTR activity in SILI is expected to provide insights into the pathogenesis of the disease and offer valuable guidance for clinical treatment. However, reliable tools for monitoring mitochondrial NTR variations and assessing treatment responses in SILI are still lacking.

Results: In this study, a mitochondria-targeting, two-photon Ir(III) complex-based probe, Cym-Ir-NTR, was designed and synthesized for accurate detection of mitochondrial NTR. Cym-Ir-NTR displayed weak luminescence due to the strong electron-withdrawing effect of the nitro group. Under hypoxic conditions, the nitro group is reduced to an amino group, yielding Cym-Ir-AMN, accompanied by significant luminescence enhancement. Molecular docking analysis indicated that Cym-Ir-NTR can be effectively catalyzed by NTR. Cym-Ir-NTR demonstrated high sensitivity, excellent selectivity, and rapid luminescence response to NTR. With its low toxicity and superior mitochondrial-targeting properties, Cym-Ir-NTR enabled successful imaging of mitochondrial NTR in living cells. Notably, leveraging Cym-Ir-NTR as an imaging probe, variations in mitochondrial NTR levels during SILI progression and the therapeutic effect of PHD inhibitors (dimethyloxalylglycine and roxadustat) on SILI were successfully monitored for the first time.

Significance: These findings confirm Cym-Ir-NTR's capability as a robust imaging tool for tracking mitochondrial NTR and evaluating treatment response of SILI to drugs. Additionally, probe Cym-Ir-NTR can be used to reveal the biological roles that mitochondrial NTR plays in SILI and offer valuable guidance for the prevention and treatment of SILI.