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Drug Screening of Nitroreductase Modulators Using an Atomic-Engineered Activatable Fluorescent Probe for Tumor
Fei Han1, Suntao Shi1, Liangying Mi1
1State Key Laboratory of Natural Product Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Abstract:
Nitroreductase (NTR), a hypoxia-upregulated enzyme, is a promising biomarker for solid tumors, driving demand for effective biosensors. Cyanine dyes are prominent fluorophores widely used in fluorescence imaging, tumor phototheranostics, and image-guided surgery. Guided by atomic engineering through strategic heteroatom substitution (C, O, and S), we designed four NTR-activated probes. Optical characterization identified HCy-NS-4 as the lead candidate, exhibiting near-infrared emission (λem = 712 nm) and over 18-fold fluorescence enhancement upon activation. The probe enabled precise imaging of hypoxic NTR and distinguished malignant from nonmalignant cells, while in vivo and in vitro studies supported the use of the probe in intraoperative tumor navigation. Additionally, using HCy-NS-4 as a screening tool, we identified luteolin as a potential NTR modulator that exhibited concentration-dependent suppression of NTR-associated fluorescence activation and significant antitumor activity in vivo. Collectively, this continuum─from atomic-scale molecular design to novel NTR inhibitor discovery─provides an innovative model for drug screening.
Insights
Researchers developed novel nitroreductase (NTR)-activated fluorescent probes for precise tumor imaging. These probes aid in distinguishing cancer cells and show potential for intraoperative navigation and drug screening.
Area of Science:
- Biomedical Engineering
- Chemical Biology
- Molecular Imaging
Background:
- Nitroreductase (NTR) is a hypoxia-upregulated enzyme and a potential biomarker for solid tumors.
- Effective biosensors are needed for NTR detection, driving interest in fluorescent probes.
- Cyanine dyes are versatile fluorophores used in various biomedical applications.
Purpose of the Study:
- To design and synthesize novel NTR-activated fluorescent probes using atomic engineering.
- To evaluate the lead probe (HCy-NS-4) for its optical properties and imaging capabilities.
- To explore the potential of the probe in intraoperative tumor navigation and drug screening.
Main Methods:
- Atomic engineering via heteroatom substitution (C, O, S) to design four NTR-activated probes.
- Optical characterization of probes, including fluorescence enhancement and emission wavelength.
- In vitro and in vivo studies for imaging hypoxic NTR, distinguishing cell types, and assessing tumor navigation.
Main Results:
- HCy-NS-4 was identified as the lead probe with near-infrared emission (712 nm) and >18-fold fluorescence enhancement.
- The probe enabled precise imaging of hypoxic NTR and differentiation of malignant from nonmalignant cells.
- Luteolin was identified as an NTR modulator with antitumor activity, using HCy-NS-4 as a screening tool.
Conclusions:
- The developed NTR-activated probes are effective tools for precise tumor imaging and intraoperative navigation.
- HCy-NS-4 demonstrates significant potential for distinguishing tumor tissues and guiding surgical procedures.
- This study presents a novel model for drug screening by combining molecular design with inhibitor discovery.
