Investigation of Carbamide Peroxide to Enhance the Therapeutic Effect of Radiodynamic Therapy
Abstract
Purpose
5-aminolevulinic acid (5-ALA)-mediated radiodynamic therapy (RDT), which integrates principles of radiotherapy and photodynamic therapy, exploits the effective tumoricidal capabilities of x-ray irradiation and the activation of protoporphyrin IX (PpIX) metabolized from 5-ALA. During x-ray irradiation in-vitro, PpIX catalyzes carbamide peroxide (PRX) to generate 1O2, thereby increasing the catalytic yield of ROS. Moreover, the emission of Cherenkov light that activates PpIX increases with higher photon energy in ex-vivo tissues. Based on this, our study aimed to investigate tumor response and the impact of PRX as a coenzyme catalyst in 5-ALA RDT using 6–45 MV photon radiation in an in-vivo mouse model.
Methods
A preclinical in-vivo murine model of small-cell lung cancer in immunocompetent C57BL/6 mice was examined. The tumors (n=320) were randomized into 16 groups (20 tumors/group), consisting of individual and possible combinations of control (untreated), 5-ALA, PRX, and radiation treatment (RT) with 6, 18, or 45 MV photons. A single fraction of 4 Gy was delivered to the tumors. 5-ALA was administered intravenously at 100 mg/kg 4 hours prior to irradiation. PRX was injected intratumorally at 60 mg/kg approximately 5 minutes before RT. Tumor volumes were monitored with a 1.5T MRI scanner over 14 days.
Results
Exceptional properties of RDT (5-ALA+RT) were observed compared to the conventional RT. An additional decrease in tumor growth was observed in RDT as the photon energy used increased. Moreover, when PRX was introduced into RDT, tumor growth delay was effectively prolonged. PRX had no effect on RT, and neither injected PRX nor 5-ALA elicited immune responses in the mice.
Conclusion
The energy dependence of RDT and the catalytic effect of PpIX with PRX were observed in-vivo 5-ALA RDT. The results suggest that higher-energy photon beams activate PpIX more effectively, and the additional ROS produced by PRX prolongs the tumor growth delay.