Enzyme‐Activatable Near‐Infrared Hemicyanines as Modular Scaffolds for in vivo Photodynamic Therapy

Photodynamic therapy is an anti‐cancer treatment that requires illumination of photosensitizers to induce local cell death. Current near‐infrared organic photosensitizers are built from large and non‐modular structures that cannot be tuned to improve safety and minimize off‐target toxicity. This work describes a novel chemical platform to generate enzyme‐activatable near‐infrared photosensitizers. We optimized the Se‐bridged hemicyanine scaffold to include caging groups and biocompatible moieties, and generated cathepsin‐triggered photosensitizers for effective ablation of human glioblastoma cells. Furthermore, we demonstrated that enzyme‐activatable Se‐bridged hemicyanines are effective photosensitizers for the safe ablation of microtumors in vivo, creating new avenues in the chemical design of targeted anti‐cancer photodynamic therapy agents. We describe a modular chemical platform for the synthesis of targeted near‐infrared photosensitizers including enzymatic cages and biocompatible units. We demonstrated its utility with the design of a cathepsin B‐activatable agent for safe ablation of microtumors in vivo in a zebrafish preclinical model.