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 O 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.