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A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging

Nitroreductases (NTRs) are known to be able to metabolize nitro-substituted compounds in the presence of reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. NTRs are present in a wide range of bacterial genera and, to a lesser extent, in eukaryotes hypoxic tumour cells and tumorou...

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Autores principales: Liu, Yun, Zhang, Leilei, Nazare, Marc, Yao, Qingqiang, Hu, Hai-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989822/
https://www.ncbi.nlm.nih.gov/pubmed/29881679
http://dx.doi.org/10.1016/j.apsb.2017.11.001
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author Liu, Yun
Zhang, Leilei
Nazare, Marc
Yao, Qingqiang
Hu, Hai-Yu
author_facet Liu, Yun
Zhang, Leilei
Nazare, Marc
Yao, Qingqiang
Hu, Hai-Yu
author_sort Liu, Yun
collection PubMed
description Nitroreductases (NTRs) are known to be able to metabolize nitro-substituted compounds in the presence of reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. NTRs are present in a wide range of bacterial genera and, to a lesser extent, in eukaryotes hypoxic tumour cells and tumorous tissues, which makes it an appropriate biomarker for an imaging target to detect the hypoxic status of cancer cells and potential bacterial infections. To evaluate the specific activation level of NTR, great efforts have been devoted to the development of fluorescent probes to detect NTR activities using fluorogenic methods to probe its behaviour in a cellular context; however, NTR-responsive MRI contrast agents are still by far underexplored. In this study, para-nitrobenzyl substituted T(1)-weighted magnetic resonance imaging (MRI) contrast agent Gd-DOTA-PNB (probe 1) has been designed and explored for the possible detection of NTR. Our experimental results show that probe 1 could serve as an MRI-enhanced contrast agent for monitoring NTR activity. The in vitro response and mechanism of the NTR catalysed reduction of probe 1 have been investigated through LC–MS and MRI. Para-nitrobenzyl substituted probe 1 was catalytically reduced by NTR to the intermediate para-aminobenzyl substituted probe which then underwent a rearrangement elimination reaction to Gd-DOTA, generating the enhanced T(1)-weighted MR imaging. Further, LC–MS and MRI studies of living Escherichia coli have confirmed the NTR activity detection ability of probe 1 at a cellular level. This method may potentially be used for the diagnosis of bacterial infections.
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spelling pubmed-59898222018-06-07 A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging Liu, Yun Zhang, Leilei Nazare, Marc Yao, Qingqiang Hu, Hai-Yu Acta Pharm Sin B Short Communication Nitroreductases (NTRs) are known to be able to metabolize nitro-substituted compounds in the presence of reduced nicotinamide adenine dinucleotide (NADH) as an electron donor. NTRs are present in a wide range of bacterial genera and, to a lesser extent, in eukaryotes hypoxic tumour cells and tumorous tissues, which makes it an appropriate biomarker for an imaging target to detect the hypoxic status of cancer cells and potential bacterial infections. To evaluate the specific activation level of NTR, great efforts have been devoted to the development of fluorescent probes to detect NTR activities using fluorogenic methods to probe its behaviour in a cellular context; however, NTR-responsive MRI contrast agents are still by far underexplored. In this study, para-nitrobenzyl substituted T(1)-weighted magnetic resonance imaging (MRI) contrast agent Gd-DOTA-PNB (probe 1) has been designed and explored for the possible detection of NTR. Our experimental results show that probe 1 could serve as an MRI-enhanced contrast agent for monitoring NTR activity. The in vitro response and mechanism of the NTR catalysed reduction of probe 1 have been investigated through LC–MS and MRI. Para-nitrobenzyl substituted probe 1 was catalytically reduced by NTR to the intermediate para-aminobenzyl substituted probe which then underwent a rearrangement elimination reaction to Gd-DOTA, generating the enhanced T(1)-weighted MR imaging. Further, LC–MS and MRI studies of living Escherichia coli have confirmed the NTR activity detection ability of probe 1 at a cellular level. This method may potentially be used for the diagnosis of bacterial infections. Elsevier 2018-05 2017-12-06 /pmc/articles/PMC5989822/ /pubmed/29881679 http://dx.doi.org/10.1016/j.apsb.2017.11.001 Text en © 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Short Communication
Liu, Yun
Zhang, Leilei
Nazare, Marc
Yao, Qingqiang
Hu, Hai-Yu
A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title_full A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title_fullStr A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title_full_unstemmed A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title_short A novel nitroreductase-enhanced MRI contrast agent and its potential application in bacterial imaging
title_sort novel nitroreductase-enhanced mri contrast agent and its potential application in bacterial imaging
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989822/
https://www.ncbi.nlm.nih.gov/pubmed/29881679
http://dx.doi.org/10.1016/j.apsb.2017.11.001
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