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A Novel NIR Fluorescent Probe for Highly Selective Detection of Nitroreductase and Hypoxic-Tumor-Cell Imaging.

ABSTRACT: Nitroreductase as a potential biomarker for aggressive tumors has received extensive attention. In this work, a novel NIR fluorescent probe for nitroreductase detection was synthesized. The probe Py-SiRh-NTR displayed excellent sensitivity and selectivity. Most importantly, the confocal fluorescence imaging demonstrated that HepG-2 cells treated with Py-SiRh-NTR under hypoxic conditions showed obvious enhanced fluorescence, which means that the NTR was overexpressed under hypoxic conditions. Moreover, the probe showed great promise that could help us to study related anticancer mechanisms research.

SUBMITTER: Liu F

PROVIDER: S-EPMC8347683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hypoxia (pO2 ? ~1.5%) is an important characteristic of tumor microenvironments that directly correlates with resistance against first-line therapies and tumor proliferation/infiltration. The ability to accurately identify hypoxic tumor cells/tissue could afford tailored therapeutic regimens for personalized treatment, development of more-effective therapies, and discerning the mechanisms underlying disease progression. Fluorogenic constructs identifying aforesaid cells/tissue operate by targeting the bioreductive activity of primarily nitroreductases (NTRs), but collectively present photophysical and/or physicochemical shortcomings that could limit effectiveness. To overcome these limitations, we present the rational design, development, and evaluation of the first activatable ultracompact xanthene core-based molecular probe (NO 2 -Rosol) for selectively imaging NTR activity that affords an "OFF-ON" near-infrared (NIR) fluorescence response (> 700 nm) alongside a remarkable Stokes shift (> 150 nm) via NTR activity-facilitated modulation to its energetics whose resultant interplay discontinues an intramolecular d-PET fluorescence-quenching mechanism transpiring between directly-linked electronically-uncoupled ?-systems comprising its components. DFT calculations guided selection of a suitable fluorogenic scaffold and nitroaromatic moiety candidate that when adjoined could (i) afford such photophysical response upon bioreduction by upregulated NTR activity in hypoxic tumor cells/tissue and (ii) employ a retention mechanism strategy that capitalizes on an inherent physical property of the NIR fluorogenic scaffold for achieving signal amplification. NO 2 -Rosol demonstrated 705 nm NIR fluorescence emission and 157 nm Stokes shift, selectivity for NTR over relevant bioanalytes, and a 28-/12-fold fluorescence enhancement in solution and between cells cultured under different oxic conditions, respectively. In establishing feasibility for NO 2 -Rosol to provide favorable contrast levels in solutio/vitro, we anticipate NO 2 -Rosol doing so in preclinical studies.

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A Novel NIR Fluorescent Probe for Highly Selective Detection of Nitroreductase and Hypoxic-Tumor-Cell Imaging.

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