Photophysical Tuning of N‑Oxide-Based Probes Enables Ratiometric Photoacoustic Imaging of Tumor Hypoxia

Hypoxia results when the oxygen supply to rapidly growing tumors becomes inadequate to support various physiological processes. This plays a role in tumor metastasis and treatment resistance. Therefore, identifying tumor hypoxia can guide treatment planning and predict patient responses. However, hypoxic volumes are heterogeneously dispersed throughout a tumor, making it a challenge to pinpoint them with any degree of accuracy. Herein, we report the development of ratiometric hypoxia probe 1 (rHyP-1), which is a hypoxia-responsive small-molecule probe designed for reliable hypoxia detection using photoacoustic imaging. Photoacoustic imaging utilizes near-infrared (NIR) light to induce the production of ultrasound signals, enabling high-resolution image acquisition at centimeter depths. Together with the ratiometric capability of rHyP-1, reliable hypoxia detection with unprecedented spatial resolution is possible while minimizing error associated with concentration dependence and tissue heterogeneity.