Abstract
Hypoxia is a characteristic of locally advanced solid tumors, resulting from an imbalance between oxygen consumption and supply. In hypoxic solid tumors, an increased expression of nitroreductase (NTR) is detected, therefore, the development of NTR-targeted fluorescent probes to selectively and efficiently detect hypoxia in vivo is of utmost importance. In this study, a probe (1) has been designed and tested for effective optical detection of NTR in vitro and in vivo. The reduction of probe (1), catalyzed by NTR, resulted in changes of the electron-withdrawn nitrogen group into an electron-donation amino group. In addition, breakage of the O-C bond ensured selective fluorescence enhancement. The in vitro response towards exogenous NTR, from rat liver microsomes, resulted in the optical enhancement during the detection process. In vivo imaging of caerorhabditis elegans (C.elegan) further confirmed the detection of NTR by probe (1). Moreover, probe (1) was successfully used for the detection of hypoxia in both HI5 cells, and a murine tumor model, which demonstrates the potential of probe (1) for application in fluorescence bioimaging studies, and tumor hypoxia diagnosis.
Highlights
Nitroreductases (NTRs) are a family of flavin-containing enzymes that catalyze the reduction of nitroaromatic compounds to the corresponding amines using either NADH or NADPH as a source of reducing equivalents[1, 2]
The large electronic change resulting from the conversion of the electron-withdrawn nitro group to the electron-donation amino group leads to breakage of the O-C bond, which ensures recovery of the fluorescence signal and an ‘off-on’ recognition strategy
We hypothesized that the probe could monitor intracellular hypoxic levels, and be used to investigate the relation between the hypoxic status and NTR expression level in cells, C. elegans and tumor tissues
Summary
Nitroreductases (NTRs) are a family of flavin-containing enzymes that catalyze the reduction of nitroaromatic compounds to the corresponding amines using either NADH or NADPH as a source of reducing equivalents[1, 2]. The development of sensors that detect NTRs have attracted much attention because of theirpotentialto detect the hypoxic status of a tumor[17,18,19,20] In these newly generated fluorescent probes, a selective ‘switch’ mechanism is used. The large electronic change resulting from the conversion of the electron-withdrawn nitro group to the electron-donation amino group leads to breakage of the O (or N)-C bond, which ensures recovery of the fluorescence signal and an ‘off-on’ recognition strategy This reaction-based sensing mechanism guarantees that the probes have high selectivity towards NTRs. in vivo applications of NTR probes for selective imaging,and therapy of intracellular hypoxia are challenging. Probe (1) maybe a promisingtool for monitoring intracellular hypoxic levels, and maybe used for measuringthe hypoxic state in tumors
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