Dual Sensitization Enables Synergistic Photodynamic Therapy and Radiotherapy for Breast Cancer
Poster
zhangyingying_aapm2026.pdf Hosted by AAPM · 2.9 MBAbstract
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.