Conspectus Drug-induced acute liver injury (DIALI) is increasingly recognized as a significant cause of acute liver injury (ALI), which is characterized by a rapid loss of hepatocyte function in patients without pre-existing liver diseases. Evaluation of corresponding biomarkers, including alanine transaminase and aspartate amino transferase, is available as a diagnostic tool for hepatotoxicity. However, these blood tests have certain limitations: (1) they are generally not available for early estimation; (2) it is difficult to visualize and identify hepatotoxicity unambiguously in real-time; and (3) the biomarkers are not unique and are usually influenced by a variety of diseases, leading to potential false results. It is of grave importance and burgeoning demand to develop an early diagnostic approach for such diseases, but the ideal toolkit remains an unresolved challenge. As an alternative, molecular optical probes (fluorescence, chemiluminescence, bioluminescence, etc.) display a lot of advantages, such as high sensitivity, noninvasive fast analysis, and real-time in situ detection. They have emerged as potent and promising tools for the biomedical study of DIALI in living system. Until now, a number of optical probes for DIALI have been reported with some great potential for clinical trials. However, most of the probes still suffer from false signals because of the limitations in clinical application, including poor selectivity, low sensitivity, and biocompatibility. One key challenge that probes face in the ALI environment is the excessive exposure to reactive oxygen/nitrogen species and diffusivity, which may lead to false-positive or negative signals. Our group has employed multiple rational approaches to engineer high-performance optical probes for DIALI. With such development, we have successfully achieved the accurate detection of DIALI with minimal false signals both ex vivo and in vivo. While marching firmly toward understanding the biogenesis and progression of DIALI, we ultimately aim at the early stage clinical diagnosis of the disease, as well as mechanism understanding for clinical trials. In this Account, we summarize and present our three new approaches for the development of high-fidelity optical probes: (1) a combined screening and rational design strategy, (2) a double-locked probe design strategy, and (3) in situ imaging based on the release of a precipitating fluorochrome strategy. Using these strategies, we have formulated probes for a range of biological species that are biomarkers of DIALI, including reactive nitrogen species (ONOO–), reactive sulfur species (H2S and H2S n ), and enzymes (LAP, MAO, and ALP). We have highlighted the rationale for our design and screening strategy and methods to achieve high-fidelity optical probes. Some recent examples of optical probes developed by our laboratory and collaborations are mainly illustrated herein. We anticipate the strategies summarized here to inspire future molecular optical probe design, to contribute to studies of the detailed molec...
Chemodynamic therapy is an emerging tumor therapeutic strategy. However, the anticancer effects are greatly limited by the strong acidity requirements for effective Fenton‐like reaction, and the inevitably “off‐target” toxicity. Herein, we develop an acidity‐unlocked nanoplatform (FePt@FeOx@TAM‐PEG) that can accurately perform the high‐efficient and tumor‐specific catalysis for anticancer treatment, through dual pathway of cyclic amplification strategy. Notably, the pH‐responsive peculiarity of tamoxifen (TAM) drug allows for the catalytic activity of FePt@FeOx to be “turn‐on” in acidic tumor microenvironments, while keeping silence in neutral condition. Importantly, the released TAM within cancer cells is able to inhibit mitochondrial complex I, leading to the upregulated lactate content and thereby the accumulated intracellular H+, which can overcome the intrinsically insufficient acidity of tumor. Through the positive feedback loop, large amount of active FePt@FeOx nanocatalyzers are released and able to access to the endogenous H2O2, exerting the improved Fenton‐like reaction within the more acidic condition. Finally, such smart nanoplatform enables self‐boosting generation of reactive oxygen species (ROS) and induces strong intracellular oxidative stress, leading to the substantial anticancer outcomes in vivo, which may provide a new insight for tumor‐specific cascade catalytic therapy and reducing the “off‐target” toxicity to surrounding normal tissues.
We developed ac yclic amplification method for an organic afterglow nanoreporter for the real-time visualization of self-generated reactive oxygen species (ROS). We promoted semiconducting polymer nanoparticles (PFODBT) as acandidate for emitting near-infrared afterglow luminescence.I ntroduction of ac hemiluminescent substrate (CPPO) into PFODBT (PFODBT@CPPO) resulted in as ignificant enhancement of afterglow intensity through the dual cyclic amplification pathway involving singlet oxygen ( 1 O 2 ). 1 O 2 produced by PFODBT@CPPO induced cancer cell necrosis and promoted the release of damage-related molecular patterns,t hereby evoking immunogenic cell death (ICD)-associated immune responses through ROS-based oxidative stress. The afterglow luminescent signals of the nanoreporter were well correlated with light-driven 1 O 2 generation and anti-cancer efficiency.T his imaging strategy provides an on-invasive tool for predicting the therapeutic outcome that occurs during ROSmediated cancer therapy.
Peroxynitrite (ONOO − ), a highly reactive species, is profoundly involved in many physiological and pathological processes. Change of the ONOO − level usually indicates an abnormal body function. Thus, it is desired to develop a highly reliable ONOO − assay to elucidate its roles in a related disease environment. In this work, we have constructed a ratiometric molecule fluorescent probe RTFP toward ONOO − with high specificity by the combination strategy of probe screening and a rational design method. RTFP displayed excellent detection sensitivity (detection limit: 4.1 nM) and produced a highly ratiometric emission signal (130-fold). Leveraging this probe, we showed the change of ONOO − content in the free-fatty-acid-induced nonalcoholic fatty liver disease (NAFLD) and acetaminophen-induced drug-induced liver injury (DILI) cellular model and for the f irst time disclosed the involved mechanism of cytochrome P450 2E1 (CYP2E1) enzyme in NAFLD with a DILI pathological environment. Furthermore, RTFP also was utilized to visualize ONOO − fluctuation of living liver tissues in a high-fat-diet-caused NAFLD model. We expected that this probe may help the study of liver injury in the exploration of mechanism and signal path.
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