De Novo Design of Photosensitizers Activated by Tumor Microenvironments for NIR Imaging and Photodynamic Therapy of Tumor

Photodynamic therapy (PDT) has emerged as a commonly employed treatment for cancer patients. However, existing photosensitizers exhibit inadequate selectivity toward cancer cells and are susceptible to penetration depth. Herein, we de novo designed an activatable photosensitizer theranostic platform (<b>SHDI</b>), extended the excitation light to the near-infrared (NIR) region, which contained an iodinated thiohemicyanine moiety as the strong photosensitizing fluorophore and a hydroxyl as the regulated group. The fluorescence emission and singlet oxygen generation of the activatable photosensitizer were inhibited by a hydroxyl-protected quencher unit, yet both of them can be concurrently activated by various substances associated with the cancer microenvironment. Based on the activatable photosensitizer platform, we prepared different theranostic agents (<b>SHDI-H</b>_<b>2</b><b>O</b>_<b>2</b>, <b>SHDI-Cys</b>, and <b>SHDI-hNQO1</b>) and demonstrated the visualization of tumor-associated biological oxidized species (H₂O₂), thiol (Cys), and enzyme (hNQO1), respectively. The agent <b>SHDI-hNQO1</b> can be effectively activated and visualized in HCT-116 transplanted colorectal cancer (CRC) in mice. Importantly, efficient PDT of <b>SHDI-hNQO1</b> has also yielded successful outcomes in the realm of in vivo antitumor treatment. The activable NIR photosensitizer theranostic platform is promising for practical colon cancer diagnosis and therapy.