Dual Sensitization Enables Synergistic Photodynamic Therapy and Radiotherapy for Breast Cancer
Abstract
Purpose
Radiotherapy (RT) and photodynamic therapy (PDT) for breast cancer are limited by tumor hypoxia and suboptimal photosensitizer performance.
Methods
We developed folate-modified copper-doped carbon dots (FC) and loaded them with 5-aminolevulinic acid (ALA) to yield FCA, a nanoplatform that executes cascade nanozyme activities to remodel the tumor microenvironment: decomposing H₂O₂ to relieve hypoxia, generating hydroxyl radicals and singlet oxygen (¹O₂), and depleting glutathione (GSH). This priming enabled efficient ALA-to-protoporphyrin IX (PpIX) conversion, which subsequently amplified reactive oxygen species (ROS) generation. The elevated oxidative stress then synergized with RT to accumulate DNA double-strand breaks and trigger cell-cycle arrest.
Results
Consequently, FCA-PDT-RT reduced 4T1 cell viability to 20.09% and induced 83.82% apoptosis-outcomes mechanistically linked to NRF2-KEAP1-HMOX1 pathway activation. Despite compensatory upregulation of antioxidant genes (HMOX1, GCLM), intracellular GSH and adenosine triphosphate (ATP) were severely depleted, establishing a metabolic crisis wherein synthesis could not match consumption. This redox/energy collapse drove the pronounced cytotoxicity observed. In an orthotopic 4T1 model, FCA-PDT-RT achieved superior tumor control at only 12 Gy, which correlated with increased CD3⁺/CD8⁺ T-cell infiltration and suppressed angiogenesis, while maintaining favorable safety.
Conclusion
FCA thus enables synergistic PDT-RT through sequential microenvironment remodeling, oxidative amplification, and metabolic exhaustion, offering a dose-sparing strategy with translational promise for breast cancer therapy.