An edoplasmic reticulum-targeted NIR fluorescent probe with a large Stokes shift for hypoxia imaging

Area of Science:

• Biomedical Engineering
• Molecular Imaging
• Chemical Biology

Background:

• Hypoxia is a critical factor in various diseases, particularly solid tumors.
• Nitroreductase (NTR) upregulation under hypoxia serves as a potential biomarker for disease states.
• Targeting the endoplasmic reticulum is crucial for understanding cellular stress responses.

Purpose of the Study:

• To develop the first endoplasmic reticulum-targeting near-infrared (NIR) fluorescent probe for nitroreductase (NTR) detection.
• To achieve highly selective and sensitive detection of NTR in biological systems.
• To provide an advanced imaging tool for studying hypoxia-related diseases.

Main Methods:

• Synthesis and characterization of the ISO-NTR fluorescent probe based on a dicyanoisophorone derivative.
• Evaluation of probe properties including Stokes shift, fluorescence intensity changes, and endoplasmic reticulum targeting efficiency (Pearson's correlation coefficient).
• Molecular docking simulations to assess probe-NTR binding affinity and selectivity.

Main Results:

• The ISO-NTR probe exhibits a large Stokes shift (185 nm) and a 5-fold increase in fluorescence intensity upon NTR binding.
• Excellent endoplasmic reticulum targeting was confirmed in living systems with high Pearson's correlation coefficients (Rr = 0.9489).
• High selectivity for NTR was supported by molecular docking, showing strong binding energy (-10.78 kcal·mol⁻¹).

Conclusions:

• The developed ISO-NTR probe is a sensitive and selective tool for NTR detection, particularly within the endoplasmic reticulum.
• Its successful application in vitro and in vivo imaging demonstrates its potential for studying NTR's role in hypoxia and related diseases.
• ISO-NTR offers a promising imaging modality for exploring endoplasmic reticulum stress in the pathogenesis of diseases like cancer.