Boosting PDT with DPA-NI-Bu: high photocytotoxicity through redox homeostasis perturbation.

Photodynamic therapy (PDT) is a promising cancer treatment that relies on reactive oxygen species (ROS) to disrupt cellular redox homeostasis, ultimately leading to cell death. The thioredoxin (Trx) system is a pivotal regulatory system for antioxidant defence, which plays a key role in immune response and cell death. Thus, perturbating the Trx system could enhance the efficacy of PDT. Naphthalimide skeletons are research hotspots in photosensitizers due to their tunable photophysical properties and high ROS yield. A series of novel photosensitizers based on naphthalimide skeletons were designed and synthesized here. Photocytotoxicity assays demonstrated that most compounds possessed considerable photosensitive effects, and DPA-NI-Bu exhibited the highest photocytotoxicity (phototoxicity index > 66.23) with IC₅₀ values of 1.51 ± 0.32 μM upon light activation. Mechanistic studies revealed that DPA-NI-Bu significantly disrupts intracellular redox homeostasis by disrupting the Trx system and glutathione (GSH) system, thereby promoting apoptosis. Furthermore, clone formation assays showed that DPA-NI-Bu exerted a potent photodynamic effect, inhibiting tumor cell proliferation by 94.9 ± 2.8%. These findings highlight the significant improvement in photosensitizing properties through structural modification and offer valuable insights for designing more effective photosensitizers for PDT applications.