Investigating Tumor Response and Efficacy of 5-Aminolevulinic Acid-Mediated Radiodynamic Therapy: Utilizing Photon Irradiation, Activation of Photosensitizer and Catalytic Effects

• Published in: International journal of radiation oncology, biology, physics Vol. 120; no. 2; p. e415
• Main Authors: Yang, D.M., Cvetkovic, D., Chen, L., Ma, C.M.C.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2024
• ISSN: 0360-3016
• DOI: 10.1016/j.ijrobp.2024.07.925

5-aminolevulinic acid (5-ALA)-mediated radiodynamic therapy (RDT) has been shown to be an effective treatment option by utilizing cellular damage caused by x-ray irradiation and activating 5-ALA-metabolized protoporphyrin IX (PpIX). Based on multiple in-silico and in-vitro studies evaluating the efficacy of 5-ALA-mediated RDT, the emission of Cherenkov light, which is used for activating PpIX, depends on the photon energy; moreover, PpIX under x-ray irradiation catalyzes the conversion of peroxide (PRX) into singlet oxygen. Therefore, in need of investigating in-vivo 5-ALA-mediated RDT, this study presents tumor response, energy dependency, catalytic effect, and normal tissue toxicity of 5-ALA-medicated RDT. The study used a subcutaneous xenograft model on immunocompetent mice. Tumors were randomized into multiple groups that included control (untreated) and various combinations of radiation treatment (RT), 5-ALA, and PRX. A total of 11 groups with 36-50 tumors per group were performed: 1) control (untreated), 2) 5-ALA alone, 3) 6MV radiation treatment (RT) alone, 4) 15MV RT alone, 5) 45MV RT alone, 6) 6MV radiodynamic therapy (RDT, 5-ALA+RT), 7) 15MV RDT, 8) 45MV RDT, 9) 6MV RDT+PRX, 10) 15MV RDT+PRX, 11) 45MV RDT+PRX. A radiation dose of 4Gy in a single fraction was delivered using half-body irradiation using 6, 15, and 45MV photons. 5-ALA and PRX were administered at 100mg/kg intravenously 4 hours before irradiation and 60mg/kg intratumorally 3-5 minutes before irradiation, respectively. Tumor growth delay was measured using 1.5T MRI for 14 days post-treatment. RDT (5-ALA+RT) significantly improved the delay in tumor growth compared to control, 5-ALA alone, and RT alone. 45MV RDT significantly delayed in tumor growth by 51.1±3.9%, 50.7±4.0%, and 47.6±4.2% compared to the control, 5-ALA alone, and 45MV RT alone on 14 days post-treatment, respectively (P<0.001). A photon energy dependency was observed in RDT, not in RT alone. Additional tumor growth delay was measured when the tumors were irradiated with higher photon energy. 45MV RDT resulted in an additional 46.7±3.4% and 19.3±1.9% tumor growth delay compared to 6 and 15MV RDT 14 days post-treatment, respectively (P<0.001). Unlike 5-ALA, the tumors that were treated with RDT with PRX started to show the effect of PRX after 7 days post-treatment. It showed ∼19.7±0.6% tumor growth delay at 14-day post-treatment compared to RDT without PRX. The histopathologic results did not show any additional normal tissue damage among treated groups. 5-ALA-mediated RDT significantly improves the therapeutic ratio compared to conventional radiation treatment. Nevertheless, the ratio can be improved further by increasing the photon energy and introducing PRX.