Aggregation-Induced Emission Photosensitizer Synergizes Photodynamic Therapy and the Inhibition of the NF-κB Signaling Pathway to Overcome Hypoxia in Breast Cancer

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, and TNBC patients often develop resistance to endocrine or molecular targeted therapy. Thus, a search for effective treatments is urgently required. Photodynamic therapy (PDT) has been verified to be a successful therapy for cancer. However, this treatment is oxygen-consuming, thus considerably limiting the PDT outcomes. The present study introduced a multistage drug delivery system to alleviate hypoxia and enhance PDT efficiency. Specifically, aggregation-induced emission luminogen (AIEgen) TPE-Py was first introduced to achieve PDT properties, and natural naphthohydroquinone dimer Rubioncolin C (RC), a blocker of mitochondria-associated oxidative phosphorylation (OXPHOS) and an NF-κB inhibitor, was applied to suppress the O2 consumption of OXPHOS and mitigate hypoxia thereafter. Enhanced PDT efficiency was validated by in vitro and in vivo TNBC models. In terms of the mechanism, AIEgen-based PDT synergized with RC could induce a fatal burst of reactive oxygen species (ROS) and ROS-mediated apoptosis. Moreover, this combination promoted the effectiveness of PDT by inhibiting the NF-κB signaling pathway. All of these results demonstrated that the administration system not only achieved a synergistic anti-TNBC effect but also expanded the clinical application of AIEgen-based PDT by overcoming hypoxia and inhibiting the NF-κB signaling pathway.