Diketopyrrolopyrrole-based sensor for over-expressed peroxynitrite in drug-induced hepatotoxicity via ratiometric fluorescence imaging

Abstract

Early diagnosis and detection of drug-induced liver injury (DILI) is great significance for the effective prevention and treatment of patients with liver injury. Studies indicate that the up-regulation of peroxynitrite (ONOO−) levels in liver is profoundly involved in acetaminophen (APAP)-induced liver injury. Herein, we constructed diketopyrrolopyrrole (DPP)-based ratiometric fluorescent probes (DPP-DH-P and DPP-DEG-P) for detecting and imaging ONOO−. Comparing two probes, DPP-DEG-P exhibited higher signal-to-noise ratio (2750-fold) and lower detection limit (3.5 nM) for tracking ONOO− in solution. DPP-DH-P possessing better biocompatibility had been successfully applied to monitor the fluctuation of ONOO− in LPS/IFN-γ or APAP-treated hepatocytes with a high signal-to-noise ratio (20-fold) by ratiometric imaging. Moreover, the probe was used to evaluate the repair effect of glutathione on DILI. We unexpectedly discovered that DPP-DH-P and DPP-DH targeted lysosomes and mitochondria, respectively. Based on the change of ONOO− induced by APAP, we observed that DPP-DH-P and the generated DPP-DH diffused from lysosome into cytoplasm, and DPP-DH did not target mitochondria due to the effect of endogenous ONOO−, these indirectly reflected the dysfunction of organelles. Observably, this work will accelerate a deeper comprehending for the pathogenesis of DILI, and furnish an effective tool for the diagnosis and treatment of DILI.