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

Abstract

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.

Ion Beam Stimulation Therapy With a Nanoradiator as a Site-Specific Prodrug

“…We demonstrated the feasibility of TIBS in animal models of these diseases with successful treatment in prior studies [7,12,14,25] and with the proposed targeted NPs in the present study, as shown in Figures 2-4. In a tumor model [7,12], we have shown that complete regression of smallsized tumors can be achieved by only proton-TIBS with a 5-10 Gy entrance dose under a given IV injection of iron oxide or gold NPs (100-300 mg/kg) without using BPD. Multiple small nodule-like lesions scattered in NT often have been encountered in various invasive cancers or in recurrences in adjacent critical function organs.…”

“…A total of 2 × 10 5 F98 glioma cells were implanted in the frontal lobe of Fischer 333 rats by stereotactic surgery as described previously [12]. Briefly, after immobilizing the rats in a rodent stereotactic frame, an incision was made in the skin, and a burr hole was made in the skull.…”

Selective magnetic resonance imaging of magnetic nanoparticles by acoustically induced rotary saturation

“…Based on our experiments, we demonstrated the sensitivity of our approach to be at least 20 Fe mg/ mL for a 5-min scan. This sensitivity is within the range of iron concentrations found in vivo within tumors of animal studies, where typical biologically acceptable dosages of iron oxide nanoparticles between 10 and 100 mg Fe/kg [well below the mouse LD50 toxicity dose of 2000 mg Fe/kg (17)], result in iron oxide accumulations in various tumors at concentrations of 20-50 mg Fe/mL (18)(19)(20).…”

Impact of Superparamagnetic Iron Oxide Nanoparticles on In Vitro and In Vivo Radiosensitisation of Cancer Cells

“…Rashid et al investigated radiosensitisation of colon cancer cells from SPIONs in combination with a 150 MeV proton beam, investigating the reactive oxygen species generation [13]. The use of iron oxide nanoparticles in combination with proton beams have also been investigated in vivo by Seo et al [57]. Choi et al found 13 nm iron oxide nanoparticles to significantly reduce the viability of colon tumour cells in mice compared with control cells when treated with 7.1 keV monochromatic x-rays [58].…”