Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model: Implication of Novel Particle Induced Radiation Therapy

Background: Proton-impact metallic nanoparticles, inducing low-energy electrons emission and characteristic X-rays termed as Coulomb nanoradiator effect (CNR), are known to produce therapeutic enhancement in proton treatment on experimental tumors. The purpose of this pilot study was to investigate the effect of CNR-based dose enhancement on tumor growth inhibition in an iron-oxide nanoparticle (FeONP)-loaded orthotopic rat glioma model. Methods: Proton-induced CNR was exploited to treat glioma-bearing SD rat loaded with FeONP by either fully-absorbed single pristine Bragg peak (APBP) or spread-out Bragg peak (SOBP) 45-MeV proton beam. A selected number of rats were examined by MRI before and after treatment to obtain the size and position information for adjusting irradiation field. Tumor regression assay was performed by histological analysis of residual tumor in the sacrificed rats 7 days after treatment. The results of CNR-treated groups were compared with the proton alone control. Results: Intravenous injection of FeONP (300 mg/kg) elevated the tumor concentration of iron up to 37 μg of Fe/g tissue, with a tumor-to-normal ratio of 5, 24 hours after injection. The group receiving FeONP and proton beam showed 65% 79% smaller tumor volume dose-dependently compared with the proton alone group. The rats receiving FeONP and controlled irradiation field by MR imaging demonstrated more than 95% 99% tumor regression compared with MRI-determined initial tumor size. Conclusions: Proton-impact FeONP produced therapeutic enhancement compared with proton alone in an orthotopic rat glioma model at a selected temporal point after treatment. Single BP proton beam could induce CNRbased dose enhancement and produce enhanced tumor regression that was comparable to SOBP treatment despite inhomogeneous tumor dose in the APBP-treated tumor. These results may suggest emergence of novel Particle Induced Radiation Therapy (PIRT) on malignant glioma.