Dual-Lock NIR Dual-Channel Probe: Synchronous Viscosity/HSO 3 – Sensing for Visualizing Platinum-Induced Nephrotoxicity and Renoprotector Screening

Platinum-based anticancer agents are extensively used in clinical chemotherapy but often cause severe nephrotoxicity, which limits their clinical utility. To address this critical challenge, we designed and validated two benzothiazole-derived near-infrared dual-channel fluorescent probes, BTXPI and BTXVI, featuring an innovative “dual-lock” mechanism. These probes adopt a channel-selective dual-lock mechanism: the red channel is a single-lock mode specifically activated by high viscosity, while the green channel is a strict dual-lock mode triggered only by the coexistence of bisulfite (HSO 3 – ) and high viscosity. These probes enable the simultaneous quantification of cellular microenvironmental viscosity and HSO 3 – concentration─two key biomarkers associated with cisplatin (DDP)-induced acute kidney injury (AKI). By comparing imaging data from confocal microscopy and super-resolution structured illumination microscopy (SIM), we further highlighted the intrinsic limitations of conventional confocal imaging in analyzing subcellular colocalization events, as it may lead to false-positive results due to diffraction limits. Using these probes, we systematically elucidated the differential nephrotoxicity of three platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) in murine models, identified DDP as the most nephrotoxic agent, and evaluated the efficacy of four renoprotective agents ( l -carnitine, N -acetylcysteine, methylprednisolone, and astragaloside IV). Notably, the combination of DDP with these renoprotective agents effectively alleviated renal injury without compromising the antitumor potency of DDP. Our dual-lock probes thus provide a robust set of chemical tools for deciphering the dynamic fluctuations of multiple pathophysiologically relevant parameters in complex biological systems, assessing drug toxicity, and optimizing combination therapeutic regimens for safe and effective cancer chemotherapy.