Activatable Phototherapeutic Prodrug Conquering Hypoxia Limitation to Enhance Chemical Drug Delivery Efficiency

Chemotherapy faces critical challenges in clinical oncology treatment. One primary reason is the tumor hypoxia that obstructs the penetration of chemotherapeutic drugs into solid tumors and diminishes drug concentration in tumor cells, leading to suboptimal treatment outcomes. Thereupon, we create a self-immolative phototherapeutic prodrug (DHQ-AZO-BIO) featured with tumor targeting and hypoxia activation. First, the prodrug is a heavy-atom-free photosensitizer based on intramolecular noncovalent interactions (NCIs), which specifically enriches into tumors and produces photocytotoxic 1O2 to eliminate normoxic tumor cells on the tumor surface layer by photodynamic therapy (PDT). Second, the PDT process also increases the hypoxic degree within the solid tumor, thereby improving the on-demand release and action efficiency of the hypoxia-sensitive prodrug. This combined treatment fashion synergizes hypoxia-activated chemotherapy with PDT to overcome the limitation of tumor hypoxia and augment the therapeutic index for tumors, contributing to the development of drug delivery systems (DDSs) and precise phototherapy for tumors.