Department of Biomedical Engineering, School of Medicine, Catholic University of Daegu, 3056-6 Taemyung 4 Dong, Nam-Ku, Daegu City, South Korea. Department of Diagnostic Imaging, School of Medicine, Catholic University of Daegu, 3056-6 Taemyung 4 Dong, Nam-Ku, Daegu City, South Korea. Department of Neurosurgery, School of Medicine, Catholic University of Daegu, 3056-6 Taemyung 4 Dong, Nam-Ku, Daegu City, South Korea.
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 CNR- based 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.
S. Seo, J. Jeon, E. Jeong, W. Chang, G. Choi and J. Kim, "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," Journal of Cancer Therapy, Vol. 4 No. 11, 2013, pp. 25-32. doi: 10.4236/jct.2013.411A004.
[1] M. M. Fitzek, A. F. Thornton, J. D. Rabinov et al., “Accelerated Fractionated Proton/Photon Irradiation to 90 Cobalt Gray Equivalent for Glioblastoma Multiforme: Results of a Phase II Prospective Trial,” Journal of Neurosurgery, Vol. 1, No. 2, 1999, pp. 251-260. http://dx.doi.org/10.3171/jns.1999. 91.2.0251 [2] M. Mizumoto, K. Tsuboi, H. Igaki et al., “Phase I/II Trial of Hyperfractionated Concomitant Boost Proton Radiotherapy for Supratentorial Glioblastoma Multiforme” International Journal of Radiation Oncology Biology Physics, Vol. 77, No. 1, 2010, pp. 98-105. http://dx.doi.org/10.1016/j.ijrobp.2009. 04.054 [3] J.-K. Kim, S.-J. Seo, H.-T. Kim, K.-H. Kim, M.-H. Chung and K.-R. Kim, “Therapeutic Application of Metallic Nanoparticles Combined with Particle-Induced X-Ray Emission Effect,” Nanotechnology, Vol. 21, No. 42, 2010, Article ID: 425102. http://dx.doi.org/10.1088/0957-4484/21/42/425102 [4] J.-K. Kim, S.-J. Seo, H.-T. Kim, K.-H. Kim, M.-H. Chung and K.-R. Kim, “Enhanced Proton Treatment in Mouse Tumors through Proton Irradiated Nanoradiator Effects on Metallic Nanoparticles,” Physics in Medicine and Biology, Vol. 57, No. 24, 2012, pp. 8309-8323. http://dx.doi.org/10.1088/0031-9155/ 57/24/8309 [5] P. C. Polf, L. F. Bronk, W. H. F. Driessen, W. Arap, R. Pasqualini and M. Gillin, “Enhanced Relative Biological Effectiveness of Proton Radiotherapy in Tumor Cells with Internalized Gold Nanoparticles,” Applied Physical Letters, Vol. 98, No. 19, 2011, Article ID: 193702. http://dx.doi.org/10.1063/ 1.3589914 [6] E. Porcel, S. Liehn, H. Remita, N. Usami, K. Kobayashi and Y. Furusawa, “Platinum Nanoparticles: A Promising Material for Future Cancer Therapy?” Nanotechnology, Vol. 21, No. 8, 2010, Article ID: 085103. http://dx.doi.org/10.1088/0957-4484/21/8/085103 [7] J.-K. Kim, S.-J. Seo, T.-J. Kim, K. Hyodo, A. Zaboronok, H. You, K. Peach and M. A. Hill, “Enhanced Generation of Reactive Oxygen Species by the Nanoradiator Effect from Core-Inner Shell Photo-Excitation or Proton Impact on Nanoparticle Atomic Clusters,” Radiation Research, 2013 submitted. [8] S.-I. Park, J.-H. Lim, Y.-H. Hwang, J.-H. Kim, C.-G. Kim and C.-O. Kim, “In Vivo and in Vitro Antitumor Activity of Doxorubicin-Loaded Magnetic Fluids,” Physica Status Solidi (c), Vol. 4, No. 12, 2007, pp. 4345-4451. [9] R. Vijayakumar, Y. Koltypin, I. Felner and A. Gedanken, “Sonochemical Synthesis and Characterization of Pure Nanometer-Sized Fe3O4 Particles,” Materials Science and Engineering: A, Vol. 286, 2000, pp. 101-105. http://dx.doi.org/10.1016/S0921-5093(00)00647-X [10] S.-J. Seo, N. Sunaguchi, T. Yuasa, Q. Huo, M. Ando, G.-H. Choi, H.-T. Kim, W.-S. Chang, K.-H. Kim, E.-J. Jeong and J.-K. Kim, “Visualization of Microvessel Proliferation as a Tumor Infiltration Structure in Rat Glioma Specimens Using the Diffraction-Enhanced Imaging In-Plane CT Technique,” Physics in Medicine and Biology, Vol. 57, No. 5, 2012, pp. 1251-1262. http://dx.doi.org/10.1088/0031-9155/ 57/5/1251 [11] J. D. Carter, N. N. Cheng, Y. Qu, G. D. Suarez and T. Guo, “Nanoscale Energy Deposition by X-Ray Absorbing Nanostructures,” Journal of Physical Chemistry B, Vol. 111, 2007, pp. 11622-11625. http://dx.doi.org/10.1021/jp075253u [12] P. Ballabh, A. Praun and M. Nedergaard, “The Blood Brain Barrier: An Overview Structure, Regulation, and Clinical Implications,” Neurobiology of Diseases, Vol. 16, No. 1, 2004, pp. 1-13.
http://dx.doi.org/10.1016/j.nbd.2003.12.016 [13] H. Wolburg, K. Wolburg-Buchholz and B. Engelhardt, “Diapedesis of Mononuclear Cells across Cerebral Venules during Experimental Autoimmune Encephalomyelitis Leaves Tight Junctions Intact,” Acta Neuropathology, Vol. 109, No. 2, 2005, pp. 181-190. http://dx.doi.org/10.1007/s00401-004-0928-x [14] D. Y. Joh, L. Sun, M. Stangl, A. Al Zaki, S. Murty, P. P. Santoiemma, J. J. Davis, B. C. Baumann, M. Alonso-Basanta, D. Bhang, G. D. Kao, A. Tsourkas and J. F. Dorsey, “Selective Targeting of Brain Tumors with Gold Nanoparticle-Induced Radiosensitization,” PLoS One, Vol. 30, No. 8, 2013, Article ID: e62425. http://dx.doi.org/10.1371/journal.pone.0062425 [15] G.-H. Choi, S.-J. Seo, K.-H. Kim, H.-T. Kim, S.-H. Park, J.-H. Lim and J.-K. Kim, “Photon Activated Therapy (PAT) Using Monochromatic Synchrotron X-Rays and Iron Oxide Nanoparticles in a Mouse Tumor Model: Feasibility Study of PAT for the Treatment of Superficial Malignancy,” Radiation Oncology, Vol. 7, 2012, p. 184. http://dx.doi.org/10.1186/1748-717X-7-184