A nitroreductase-responsive fluorescence turn-on photosensitizer for lysosomes imaging and photodynamic therapy

Jinhui Wang ¹, Ruxin Li ¹, Han Ouyang ¹

⁰Institute of Drug Discovery Technology, Ningbo University, Ningbo, 315211, China.

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May 18, 2024

View abstract on PubMed

Summary

A novel probe, M-TPE-P, effectively detects hypoxia biomarker nitroreductase (NTR) in lysosomes. It shows potential as a photosensitizer for cancer therapy via reactive oxygen species generation.

Area Of Science

Biomedical Engineering
Chemical Biology
Molecular Imaging

Background

Nitroreductase (NTR) is a key biomarker for tumor hypoxia.
Lysosomal dysfunction is linked to various diseases.
Developing targeted probes for disease assessment is crucial.

Purpose Of The Study

To design and synthesize an NTR-triggered, lysosome-targeting probe (M-TPE-P).
To evaluate M-TPE-P as a potential photosensitizer for cancer therapy.
To assess the probe's efficacy in detecting NTR and its lysosomal targeting specificity.

Main Methods

Tetraphenylethylene-based probe M-TPE-P synthesis.
Density Functional Theory (DFT) calculations for photophysical properties.
Docking studies to assess M-TPE-P affinity for NTR.
In vitro assays for selectivity, sensitivity, and detection limit.
Cell imaging and colocalization studies for lysosomal targeting.
Evaluation of reactive oxygen species (ROS) generation and photodynamic therapy (PDT) effects.

Main Results

M-TPE-P demonstrated a narrow singlet-triplet energy gap, indicating efficient photosensitization.
High selectivity and sensitivity for NTR detection across a broad pH range (kcat/Km = 2.18 × 10^4 M^-1 s^-1).
Low detection limit of 53.6 ng/mL in 80% PBS/DMSO.
Successful intracellular NTR tracing with green fluorescence and excellent lysosome-targeting specificity.
Effective ROS generation and significant PDT effect upon NIR irradiation.

Conclusions

M-TPE-P is a highly selective and sensitive probe for NTR detection, with specific lysosomal targeting.
The probe's photophysical properties and ability to generate ROS position it as a promising candidate for cancer photodynamic therapy.

Keywords:

Lysosomal imaging Nitroreductase Photodynamic therapy Tetraphenylethylene