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Mitochondrial Peroxynitrite Mediation of Anthracycline-Induced Cardiotoxicity as Visualized by a Two-Photon Near-Infrared Fluorescent Probe

Xie, Xilei, Tang, Fuyan, Liu, Guangzhao, Li, Yong, Su, Xingxing, Jiao, Xiaoyun, Wang, Xu, Tang, Bo
Analytical chemistry 2018 v.90 no.19 pp. 11629-11635
animal models, anthracyclines, biomarkers, cardiomyocytes, cardiotoxicity, drugs, fluorescent dyes, image analysis, mitochondria
Anthracyclines rank among the most efficacious anticancer medications. However, their clinical utility and oncologic efficacy are severely compromised by the cardiotoxicity risk facing the early-diagnosis difficulty and their unclear molecular mechanism. Herein, a two-photon-excitable and near-infrared-emissive fluorescent probe, TPNIR-FP, was fabricated and endowed with extraordinary specificity and sensitivity and a rapid response toward peroxynitrite (ONOO–), as well as mitochondria-targeting ability. With the aid of TPNIR-FP, we demonstrate that mitochondrial ONOO– is upregulated in the early stage and contributes to the onset and progression of anthracycline cardiotoxicity in cardiomyocyte and mouse models; therefore, it represents an early biomarker to predict subclinical cardiotoxicity induced by drug challenge. Furthermore, TPNIR-FP is proved to be a robust imaging tool to provide critical insights into drug-induced cardiotoxicity and other ONOO–-related pathophysiological processes.