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Dual-Lock NIR Dual-Channel Probe: Synchronous Viscosity/HSO3- Sensing for Visualizing Platinum-Induced Nephrotoxicity
Siyu Gao1, Lulu Zhang1, Wenwen Li2
1College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
Abstract:
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 (HSO3-) and high viscosity. These probes enable the simultaneous quantification of cellular microenvironmental viscosity and HSO3- 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.
Insights
New fluorescent probes help assess platinum drug kidney toxicity and test protective agents, aiding safer cancer chemotherapy.
Area of Science:
- Biomedical Engineering
- Chemical Biology
- Molecular Imaging
Background:
- Platinum-based chemotherapy agents, while effective, cause significant nephrotoxicity, limiting their use.
- Acute kidney injury (AKI) is a major concern in patients receiving cisplatin (DDP).
- Simultaneous monitoring of cellular microenvironment viscosity and bisulfite (HSO3-) concentration is crucial for understanding DDP-induced AKI.
Purpose of the Study:
- To design and validate novel near-infrared dual-channel fluorescent probes (BTXPI and BTXVI) for simultaneous detection of viscosity and HSO3-.
- To investigate the limitations of confocal microscopy versus super-resolution microscopy in subcellular analysis.
- To evaluate the nephrotoxicity of different platinum-based drugs and assess renoprotective agents.
Main Methods:
- Development of benzothiazole-derived fluorescent probes with a "dual-lock" mechanism.
- Utilizing confocal microscopy and super-resolution structured illumination microscopy (SIM) for cellular imaging.
- In vivo studies in murine models to assess drug toxicity and renoprotective efficacy.
Main Results:
- The dual-channel probes successfully quantified viscosity and HSO3- concentration, key biomarkers for DDP-induced AKI.
- Super-resolution microscopy revealed limitations of confocal imaging in resolving subcellular colocalization.
- Cisplatin was identified as the most nephrotoxic platinum drug; renoprotective agents combined with DDP alleviated kidney injury without reducing antitumor effects.
Conclusions:
- The developed "dual-lock" fluorescent probes are effective tools for monitoring complex biological parameters and assessing drug toxicity.
- These probes facilitate the optimization of combination therapies for safer and more effective cancer chemotherapy.
- The study highlights the importance of advanced imaging techniques for accurate subcellular analysis.
