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

Abstract

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 T1-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 T1-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.

Positron Emission Tomography Imaging of Staphylococcus aureus Infection Using a Nitro-Prodrug Analogue of 2-[18F]F-p-Aminobenzoic Acid

“…1 H NMR (400 MHz, DMSO-d 6 ): δ 1.33 (t, J = 7.09 Hz, 3 H), δ 4.37 (q, J = 7.09 Hz, 2 H), δ 8.08−8.19 (m, 2 H), δ 8.23 (dd, J = 10.51, 1.71 Hz, 1 H). 19 F NMR (376 MHz, DMSO-d 6 ): δ −106.99 (s, 1 F).…”

Rapid differentiation between bacterial infections and cancer using a near-infrared fluorogenic probe

“…9 We were in particular interested in investigating activatable molecular probes for the detection of nitroreductases (NTRs) in bacteria. [10][11][12][13][14][15] NTRs represent a family of avin-containing enzymes that are able to effectively metabolize nitrosubstituted groups into hydroxylamines or amines in the presence of reduced nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH). 16 NTRs are widely expressed in most Gram-positive and Gramnegative bacterial strains, but also in hypoxic tumour cells and tumorous tissues of eukaryotes.…”

Hypoxia-degradable and long-circulating zwitterionic phosphorylcholine-based nanogel for enhanced tumor drug delivery

“…Hypoxia changes the tumor microenvironment through the overexpressed HIF-1 α , which leads to the cancer progression and metastasis 38 , 39 . It has been reported that the azobenzene group could be cleaved with the elevated levels of reducing enzymes in hypoxic tumor microenvironment 40 .…”