Photodynamic Priming Affects the Radiation-Induced Skin Toxicity and Damage Timeline
Abstract
Purpose
This study was to examine the complimentary damage mechanisms and their potential synergy between conventional/ultrahigh dose rate radiotherapy (CDR/UHDR RT) and photodynamic therapy (PDT). FLASH radiotherapy produces a significant reduction in radiation-induced normal tissue toxicity at isodose levels when compared to CDR-RT, while maintaining the tumor control. In contrast to RT, PDT using 5-aminolevulinic acid (ALA-PDT) inducing intracellular protoporphyrin IX (PpIX), can be activated by light to produce reactive oxygen species and trigger vascular and metabolic modulations. At low doses, PDT does not induce cytotoxicity but can transiently increase blood flow, oxygenation, and local inflammation — an approach referred to as photodynamic priming (PDP) – which can be biologically complimentary to radiation damage. This study examined if PDP could modulate differential responses between CDR and UHDR irradiation.
Methods
Female C57Bl/6 mice were used in this study, with post treatment analysis to examine skin toxicity, OCT-based epidermal thickness and structural skin changes, and histological remodeling after CDR and UHDR irradiation (0.1 Gy/s CDR; 95-100 Gy/s UHDR from a 9 MeV Mobetron linac). Examinations were targeted at the times of onset for PDT/RT damage, at early (4 days), intermediate (10 days), and late-intermediate (30 days) endpoints. PDP was given by 250mg/kg ALA injection followed by 5 J/cm2 light at 635nm.
Results
Low-dose ALA-PDT priming substantially altered the temporal trajectory of radiation skin injury. A markedly earlier onset of damage (Day 4–5) was seen, suggesting that priming modified vascular and/or metabolic conditions that sensitize the skin to radiation.
Conclusion
The similarity in response acceleration for both CDR and UHDR indicated that priming affected radiation-independent pathways such as perfusion, inflammation, oxidative stress, or epithelial turnover. The combination of clinical scoring, OCT structural imaging, epidermal and dermal thickness quantification, and multi-timepoint histology provided a comprehensive framework for understanding how microenvironmental perturbation modifies RT toxicity.