A proton-catalyzing prodrug for PDT and glycolysis inhibition-synergistic therapy of tumor in spatiotemporal dimensions

The reactive oxygen species (ROS) generation from photosensitizer in photodynamic therapy (PDT) is limited by tumor hypoxia. Even type-I photosensitizers, e.g., sulfur-substituted Nile blue, still rely on oxygen as the main center for transferring electrons to generate ROS. Cutting off the pathway of oxygen consumption in tumor can help photosensitizers overcome the limitation of low oxygen, in order to efficiently generate more ROS. It is known that glycolysis inhibitor 3-bromopyruvic acid (3-BP), which could specially target mitochondria, can provide more oxygen by inhibiting oxidative phosphorylation. Herein, we successfully designed and synthesized a new 3-BP-coupled sulfur-substituted Nile blue as prodrug (NBBP) for chemical/photodynamic synergistic therapy. Major results indicated that the protons in tumor catalyzed the hydrolysis of NBBP, inhibited photoinduced electron transfer between 3-BP and the photosensitizer in NBBP and further assisted the photosensitizer to be localized in mitochondria, utilizing local oxygen as much as possible and kill tumor cells more efficiently. Moreover, the glycolysis inhibition-induced autophagy was combined with PDT-induced autophagy, which could promote the deaths of tumor cells. Unlike other remedies exploiting nanomaterials, this construction method of NBBP achieves the efficient synergy of photodynamic therapy and glycolysis inhibition, stronger than their theoretical addition, in spatiotemporal dimensions. Our study provides not only a highly efficient platform for tumor therapy but also a design approach for prodrugs with synergistic effects.