Harnessing GLUT1‐Targeted Pro‐oxidant Ascorbate for Synergistic Phototherapeutics

Abstract Despite extensive efforts to realize effective photodynamic therapy (PDT), there is still a lack of therapeutic approaches concisely structured to mitigate the major obstacles of PDT in clinical applications. Herein, we report a molecular strategy exploiting ascorbate chemistry to enhance the efficacy of PDT in cancer cells overexpressing glucose transporter 1 (GLUT1). AA‐EtNBS , a 5‐O‐substituted ascorbate–photosensitizer (PS) conjugate, undergoes a reversible structural conversion of the ascorbate moiety in the presence of reactive oxygen species (ROS) and glutathione (GSH), thereby promoting its uptake in GLUT1‐overexpressed KM12C colon cancer cells and perturbing tumor redox homeostasis, respectively. Due to the unique pro‐oxidant role of ascorbate in tumor environments, AA‐EtNBS effectively sensitized KM12C cancer cells prior to PS‐mediated generation of superoxide radicals under near‐infrared (NIR) illumination. AA‐EtNBS successfully exhibited GLUT1‐targeted synergistic therapeutic efficacy during PDT both in vitro and in vivo. Therefore, this study outlines a promising strategy employing ascorbate both as a targeting unit for GLUT1‐overexpressed cancer cells and redox homeostasis destruction agent, thereby enhancing therapeutic responses towards anticancer treatment when used in conjunction with conventional PDT.