Engineering an ultra-low background nitroreductase-activated near infrared targeted theranostic probe for lung tumor surgery navigation.

Lung cancer has become one of the most detrimental malignant tumors to human health globally. A major challenge in its management lies in the difficulty of early detection and complete resection of lesions, particularly in cases of metastatic disease. Therefore, it is urgent to develop high-performance activatable fluorescent probes to improve the diagnosis and treatment of lung cancer and its metastases. Given that nitroreductase (NTR) is recognized as a cancer-specific biomarker involved in lung tumor progression, invasion, and metastasis, we designed and synthesized a new near-infrared (NIR) fluorescent probe, NTANA, which targets both mitochondria and tumor tissues. NTANA demonstrated outstanding sensitivity and selectivity toward NTR in spectroscopic assays. At the cellular level, it showed a specific response to NTR in hypoxic tumor cells, effectively distinguishing lung cancer cells from normal cells. In vivo studies confirmed that NTANA responds robustly to hypoxic conditions in a mouse model of lung tumor, enabling clear and rapid identification of tumor margins with a high tumor-to-normal (T/N) tissue ratio of 34.8:1. Furthermore, the probe was successfully applied to detect NTR in a lung metastasis model. This work highlights the potential of enzyme-activatable NIR probes to facilitate clinical diagnosis and image-guided surgery for lung cancer.