Efficacy and Energy Dependence of Radiodynamic Therapy: 6-45MV photon beams with 5-aminolevulinic acid

There is a growing interest in radiodynamic therapy (RDT), which combines the principles of radiotherapy and photodynamic therapy (PDT) to enhance tumoricidal capabilities while limiting toxicities to healthy tissues. RDT utilizes the cellular damage caused by high-energy radiation and the photosensitizer activation within cancer cells.

5-aminolevulinic acid (5-ALA)-mediated RDT exploits the x-ray irradiation and activation of protoporphyrin IX (PpIX), which is metabolized from 5-ALA. Cherenkov light induced by megavoltage photon beams effectively activates PpIX due to the Soret band (the intense absorption peak in the blue region of the visible spectrum). The emission of Cherenkov light increases with photon energy in water and ex vivo tissues. Based on this, our study aimed to investigate the tumor response and photon efficacy of RDT combined with 5-ALA administration and megavoltage photon radiation treatment in an in vivo mouse model.

A preclinical in vivo murine small-cell lung cancer model in immunocompetent C57BL/6 mice was examined. The tumors (n = 400) were randomized into eight groups: control (untreated), 5-ALA only, 6, 15, and 45 MV radiation treatment (RT) only, and 6, 15, and 45 MV RDT (5-ALA+RT) to observe individual and synergistic effects of 5-ALA and RT. A radiation dose of 4 Gy in a single fraction was delivered to the tumors using half-body irradiation using 6, 15, and 45 MV photons. 5-ALA was injected at 100 mg/kg intravenously 4 h before irradiation. Tumor volumes were measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment, initial volume at the start of the study), and 3-, 7-, and 14-day posttreatment. Normal tissue toxicity was assessed on the hematoxylin-eosin (H&E)-stained microscope slides using the standard histopathologic score.

The most significant decrease in tumor growth was achieved 14-day posttreatment with 45 MV RDT by 52.7 ± 3.7 %, 52.4 ± 3.8 %, and 47.6 ± 4.2 % compared to the control, 5-ALA only, and 45 MV RT only, respectively (P < 0.001). Likewise, 45 MV RDT resulted in an additional 36.6 ± 4.2 % and 17.0 ± 8.1 % decrease in tumor growth compared to 6 and 15 MV RDT 14-day posttreatment, respectively (P < 0.001), whereas RT only did not show significant differences across all photon energies. Based on these results, an additional 47.3 ± 8.2 % decrease in tumor growth was estimated as a synergistic effect in the RDT groups compared to 5-ALA and RT only groups. The results of our histopathologic analysis showed similarities in normal tissue toxicities between RT and RDT.

A combination of 5-ALA administration and megavoltage photon irradiation demonstrated an enhancement of the therapeutic efficacy, potentially leading to better patient outcomes. The treatment outcome was improved with higher energy because of photon energy dependence, whereas the conventional radiation treatment was not improved. Overall, the benefit of radiation treatment and PDT was synergistic and achieved in one treatment session.