Recent progress in the design principles, sensing mechanisms, and applications of small-molecule probes for nitroreductases

Qi, Yanan; Guo, Liang; Chen, Lili; Li, Hua; Yang, Yu‐Shun; Jiang, Aiqin; Zhu, Hai‐Liang

doi:10.1016/j.ccr.2020.213460

Cited by 72 publications

(27 citation statements)

References 126 publications

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“…The detection limit of AS-Cy-NO 2 towards NTR by fluorescence was 2.5 ng mL À 1 , which is comparable to those previously reported (Table S6). [59] This demonstrated that the AS-Cy-NO 2 probe could detect the NTR level with high sensitivity.…”

Section: Methodsmentioning

confidence: 88%

A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In Vivo

et al. 2021

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Herein, we describe an energy balance strategy between fluorescence and photoacoustic effects by sulfur substitution to transform existing hemicyanine dyes (Cy) into optimized NIRF/PA dual ratiometric scaffolds. Based on this optimized scaffold, we reported the first dual-ratio response of nitroreductase probe AS-Cy-NO 2 , which allows quantitative visualization of tumor hypoxia in vivo. AS-Cy-NO 2 , composed of a new NIRF/PA scaffold thioxanthene-hemicyanine (AS-Cy-1) and a 4-nitrobenzene moiety, showed a 10-fold ratiometric NIRF enhancement (I 773 /I 733 ) and 2.4-fold ratiometric PA enhancement (PA 730 /PA 670 ) upon activation by a biomarker (nitroreductase, NTR) associated with tumor hypoxia. Moreover, the dual ratiometric NIRF/PA imaging accurately quantified the hypoxia extent with high sensitivity and high imaging depth in xenograft breast cancer models. More importantly, the 3D maximal intensity projection (MIP) PA images of the probe can precisely differentiate the highly heterogeneous oxygen distribution in solid tumor. Thus, this study provides a promising NIRF/PA scaffold that may be generalized for the dual ratiometric imaging of other disease-relevant biomarkers.

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Section: Methodsmentioning

confidence: 88%

A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In Vivo

et al. 2021

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“…Type-II NTRs catalyze the one-electron reduction process, generating the nitro anion radical, which, in the presence of oxygen, is rapidly re-oxidized to the original nitro-aromatic compound, simultaneously producing the peroxide radical. This creates a “futile redox cycle”, which can cause oxidative stress [ 21 , 91 ]. However, in an anaerobic environment, re-oxidation does not occur and the reduction of the nitro group is complete and irreversible [ 79 ] ( Figure 3 ).…”

Section: Oxidoreductasesmentioning

confidence: 99%

“…Nitroreductases are a widely studied therapeutic target for the activation of prodrugs targeting cancer cells. Moreover, it was suggested that the assessment of the NTR level could be directly employed to assess the level of hypoxia, which would help to define the disease state and the treatment prognosis [ 21 ]. Despite proposing the level of NTR in cells as an effective biomarker of hypoxia, the data on the direct relationship between the concentration of NTR and the degree of hypoxia are contradictory [ 79 , 80 ].…”

Section: Oxidoreductasesmentioning

confidence: 99%

“…Many excellent reviews present the recent findings in this field [ 14 , 17 , 18 , 19 ]. In many cases, probes for PET and OI relay on selective activation under hypoxic conditions of the tumor microenvironment ensuring not only reduced oxygen concentration, but also increased expression or activity of the relevant oxidoreductases [ 14 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging

Janczy-Cempa

Mazuryk

Kania

et al. 2022

Cancers

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Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off–on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable.

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“…The oxygen content in tumors is heterogeneously distributed, with many regions having a low oxygen pressure, which denies access of immune cells to lesion sites. 12–16 Hypoxia is also a salient feature of pathological tissue remodelling in inflammation associated with an increased metabolic demand and variability in the microenviroment. During inflammation, the hypoxia-inducible factor (HIF) is stable and transcriptionally active, 10 thus making hypoxia a proxy indicator of solid tumors and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Visualizing nitroreductase activity in living cells and tissues under hypoxia and hepatic inflammation

Wang

Cai

Wong

et al. 2022

Analyst

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Recent progress in the design principles, sensing mechanisms, and applications of small-molecule probes for nitroreductases

Cited by 72 publications

References 126 publications

A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In Vivo

A General Approach to Design Dual Ratiometric Fluorescent and Photoacoustic Probes for Quantitatively Visualizing Tumor Hypoxia Levels In Vivo

Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging

Visualizing nitroreductase activity in living cells and tissues under hypoxia and hepatic inflammation

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