Activatable near-infrared fluorogenic probe for monitoring GSH variations in synergistic PTX and RSL3 treatment of hypopharyngeal carcinoma

Hypopharyngeal carcinoma (HPC) is a class of rare squamous cell carcinomas of the head and neck that are highly aggressive and have a poor prognosis. It is mostly clinically diagnosed at an advanced stage and is pronounced resistant to chemotherapy. Ferroptosis, a class of iron-dependent programmed cell death triggered by lipid peroxidation accumulation, is regarded as a novel strategy for antitumor therapy. In this work, a novel GSH-activatable near-infrared fluorogenic (NIRF) probe, DCI-F, was screened based on a substituent-regulation strategy. This probe was successfully applied to the study of ferroptosis induced by the combination of low-dose PTX and RSL3, which demonstrated that the combination therapy synergistically accelerated GSH depletion in tumor cells. DCI-F was able to distinguish tumor cells from normal squamous cells. The combination of PTX + RSL3 reduced intratumorally GSH levels and enhanced the therapeutic efficacy compared to single-drug treatment in FaDu tumor-bearing mice model. DCI-F enabled deep tissue imaging in fresh specimens of HPC patient. This work provided a novel GSH imaging tool for the development of low-toxicity and efficient tumor synergistic treatment strategies.