Document Type : Original Research

Authors

1 PhD, Department of Radiology Technology, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran

2 PhD, Department of Radiologic Technology, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 PhD, Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

4 PhD, Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran

5 PhD, Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Abstract

Background: Radiosensitization using nanoparticles is proposed as a novel strategy for treatment of different cancers. Superparamagnetic iron oxide nanoparticles (SPIONs) have been reported to enhance effects of radiotherapy in several researches.
Objective: The objective of this research is to investigate the radiosensitization properties of polyglycerol coated SPIONs (PG-SPIONs) on U87-MG cancer cells.
Material and Methods: In this experimental study, polyglycerol coated SPIONs were synthesized by thermal decomposition method and characterized by FTIR, TEM and VSM analysis. Cellular uptake of nanoparticles by cells was examined via AAS. Cytotoxicity and radiosensitization of nanoparticles in combination with radiation were evaluated by MTT and colony assay, respectively.
Results: Mean size of nanoparticles was 17.9±2.85 nm. FTIR verified SPIONs coating by Polyglycerol and VSM showed that they have superparamagnetic behaviour. Viability significantly (P < 0.001) decreased at concentrations above 100µg/ml for SPIONs but not for PG-SPIONs (P > 0.05). Dose verification results by TLD for doses of 2 and 4 Gy were 2±0.19 and 4±0.12 Gy respectively. The combination index for all situations was less than 1 and the effect is antagonism.
Conclusion: However, PG-SPIONs combination with 6 MV X-ray reduced survival of U87-MG cells compared to radiation alone but the effect is antagonism.

Keywords

  1. Huang G, Chen H, Dong Y, Luo X, Yu H, Moore Z, et al. Superparamagnetic iron oxide nanoparticles: amplifying ROS stress to improve anticancer drug efficacy. Theranostics. 2013;3:116-26. doi: 10.7150/thno.5411. PubMed PMID: 23423156. PubMed PMCID: PMC3575592.
  2. Babaei M, Ganjalikhani M. The potential effectiveness of nanoparticles as radio sensitizers for radiotherapy. Bioimpacts. 2014;4:15-20. doi: 10.5681/bi.2014.003. PubMed PMID: 24790894. PubMed PMCID: PMC4005278.
  3. Khoei S, Mahdavi SR, Fakhimikabir H, Shakeri-Zadeh A, Hashemian A. The role of iron oxide nanoparticles in the radiosensitization of human prostate carcinoma cell line DU145 at megavoltage radiation energies. Int J Radiat Biol. 2014;90:351-6. doi: 10.3109/09553002.2014.888104. PubMed PMID: 24475739.
  4. Su XY, Liu PD, Wu H, Gu N. Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy. Cancer Biol Med. 2014;11:86-91. doi: 10.7497/j.issn.2095-3941.2014.02.003. PubMed PMID: 25009750. PubMed PMCID: PMC4069802.
  5. Retif P, Pinel S, Toussaint M, Frochot C, Chouikrat R, Bastogne T, et al. Nanoparticles for Radiation Therapy Enhancement: the Key Parameters. Theranostics. 2015;5:1030-44. doi: 10.7150/thno.11642. PubMed PMID: 26155318. PubMed PMCID: PMC4493540.
  6. Haume K, Rosa S, Grellet S, Smialek MA, Butterworth KT, Solov’yov AV, et al. Gold nanoparticles for cancer radiotherapy: a review. Cancer Nanotechnol. 2016;7:8. doi: 10.1186/s12645-016-0021-x. PubMed PMID: 27867425. PubMed PMCID: PMC5095165.
  7. Delaney GP, Barton MB. Evidence-based estimates of the demand for radiotherapy. Clin Oncol (R Coll Radiol). 2015;27:70-6. doi: 10.1016/j.clon.2014.10.005. PubMed PMID: 25455408.
  8. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol. 2010;31:363-72. doi: 10.1007/s13277-010-0042-8. PubMed PMID: 20490962.
  9. Amelio D, Amichetti M. Radiation therapy for the treatment of recurrent glioblastoma: an overview. Cancers (Basel). 2012;4:257-80. doi: 10.3390/cancers4010257. PubMed PMID: 24213239. PubMed PMCID: PMC3712688.
  10. Raizer J, Parsa A. Current understanding and treatment of gliomas: Springer; 2015.
  11. Huynh GH, Deen DF, Szoka Jr FC. Barriers to carrier mediated drug and gene delivery to brain tumors. J Control Release. 2006;110:236-59. doi: 10.1016/j.jconrel.2005.09.053. PubMed PMID: 16318895.
  12. Invernici G, Cristini S, Alessandri G, Navone SE, Canzi L, Tavian D, et al. Nanotechnology advances in brain tumors: the state of the art. Recent Pat Anticancer Drug Discov. 2011;6:58-69. PubMed PMID: 21110824.
  13. Rozhkova EA. Nanoscale materials for tackling brain cancer: recent progress and outlook. Adv Mater. 2011;23:H136-50. doi: 10.1002/adma.201004714. PubMed PMID: 21506172.
  14. Ling Y, Wei K, Zou F, Zhong S. Temozolomide loaded PLGA-based superparamagnetic nanoparticles for magnetic resonance imaging and treatment of malignant glioma. Int J Pharm. 2012;430:266-75. doi: 10.1016/j.ijpharm.2012.03.047. PubMed PMID: 22486964.
  15. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359:492-507. doi: 10.1056/NEJMra0708126. PubMed PMID: 18669428.
  16. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014;16 Suppl 4:iv1-63. doi: 10.1093/neuonc/nou223. PubMed PMID: 25304271. PubMed PMCID: PMC4193675.
  17. Fang C, Wang K, Stephen ZR, Mu Q, Kievit FM, Chiu DT, et al. Temozolomide nanoparticles for targeted glioblastoma therapy. ACS Appl Mater Interfaces. 2015;7:6674-82. doi: 10.1021/am5092165. PubMed PMID: 25751368. PubMed PMCID: PMC4637162.
  18. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5:1725-31. PubMed PMID: 231022.
  19. Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65:499-508. doi: 10.1016/j.ijrobp.2005.12.002. PubMed PMID: 16517093.
  20. Lu AH, Salabas EL, Schuth F. Magnetic nanoparticles: synthesis, protection, functionalization, and application. Angew Chem Int Ed Engl. 2007;46:1222-44. doi: 10.1002/anie.200602866. PubMed PMID: 17278160.
  21. Kanwar JR, Mahidhara G, Kanwar RK. Recent advances in nanoneurology for drug delivery to the brain. Current nanoscience. 2009;5:441-8.
  22. Pankhurst QA, Connolly J, Jones S, Dobson J. Applications of magnetic nanoparticles in biomedicine. Journal of physics D: Applied physics. 2003;36:R167.
  23. Chertok B, Moffat BA, David AE, Yu F, Bergemann C, Ross BD, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29:487-96. doi: 10.1016/j.biomaterials.2007.08.050. PubMed PMID: 17964647. PubMed PMCID: PMC2761681.
  24. Hadjipanayis CG, Machaidze R, Kaluzova M, Wang L, Schuette AJ, Chen H, et al. EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Res. 2010;70:6303-12. doi: 10.1158/0008-5472.CAN-10-1022. PubMed PMID: 20647323. PubMed PMCID: PMC2912981.
  25. Braun S, Oppermann H, Mueller A, Renner C, Hovhannisyan A, Baran-Schmidt R, et al. Hedgehog signaling in glioblastoma multiforme. Cancer Biol Ther. 2012;13:487-95. doi: 10.4161/cbt.19591. PubMed PMID: 22406999.
  26. Huang FK, Chen WC, Lai SF, Liu CJ, Wang CL, Wang CH, et al. Enhancement of irradiation effects on cancer cells by cross-linked dextran-coated iron oxide (CLIO) nanoparticles. Phys Med Biol. 2010;55:469-82. doi: 10.1088/0031-9155/55/2/009. PubMed PMID: 20023329.
  27. Klein S, Sommer A, Distel LV, Neuhuber W, Kryschi C. Superparamagnetic iron oxide nanoparticles as radiosensitizer via enhanced reactive oxygen species formation. Biochem Biophys Res Commun. 2012;425:393-7. doi: 10.1016/j.bbrc.2012.07.108. PubMed PMID: 22842461.
  28. Roeske JC, Nunez L, Hoggarth M, Labay E, Weichselbaum RR. Characterization of the theorectical radiation dose enhancement from nanoparticles. Technol Cancer Res Treat. 2007;6:395-401. doi: 10.1177/153303460700600504. PubMed PMID: 17877427.
  29. Veiseh O, Sun C, Gunn J, Kohler N, Gabikian P, Lee D, et al. Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett. 2005;5:1003-8. doi: 10.1021/nl0502569. PubMed PMID: 15943433.
  30. Hu F, Neoh KG, Cen L, Kang ET. Cellular response to magnetic nanoparticles “PEGylated” via surface-initiated atom transfer radical polymerization. Biomacromolecules. 2006;7:809-16. doi: 10.1021/bm050870e. PubMed PMID: 16529418.
  31. Lutz JF, Stiller S, Hoth A, Kaufner L, Pison U, Cartier R. One-pot synthesis of pegylated ultrasmall iron-oxide nanoparticles and their in vivo evaluation as magnetic resonance imaging contrast agents. Biomacromolecules. 2006;7:3132-8. doi: 10.1021/bm0607527. PubMed PMID: 17096542.
  32. Frey H. Hyperbranched polyglycerols (Synthesis and Applications). Encyclopedia of Polymeric Nanomaterials. 2015:977-80.
  33. Saucier-Sawyer JK, Deng Y, Seo YE, Cheng CJ, Zhang J, Quijano E, et al. Systemic delivery of blood-brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue. J Drug Target. 2015;23:736-49. doi: 10.3109/1061186X.2015.1065833. PubMed PMID: 26453169. PubMed PMCID: PMC4860350.
  34. Deng Y, Saucier-Sawyer JK, Hoimes CJ, Zhang J, Seo YE, Andrejecsk JW, et al. The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. Biomaterials. 2014;35:6595-602. doi: 10.1016/j.biomaterials.2014.04.038. PubMed PMID: 24816286. PubMed PMCID: PMC4062180.
  35. Maity D, Choo S-G, Yi J, Ding J, Xue JM. Synthesis of magnetite nanoparticles via a solvent-free thermal decomposition route. Journal of Magnetism and Magnetic Materials. 2009;321:1256-9.
  36. Zhao L, Chano T, Morikawa S, Saito Y, Shiino A, Shimizu S, et al. Hyperbranched polyglycerol-grafted superparamagnetic iron oxide nanoparticles: synthesis, characterization, functionalization, size separation, magnetic properties and biological applications. Advanced Functional Materials. 2012;22:5107-17.
  37. Indira T, Lakshmi P. Magnetic nanoparticles—a review. Int J Pharm Sci Nanotechnol. 2010;3:1035-42.
  38. Mody VV, Cox A, Shah S, Singh A, Bevins W, Parihar H. Magnetic nanoparticle drug delivery systems for targeting tumor. Applied Nanoscience. 2014;4:385-92.
  39. Han L, Shi S, Gong T, Zhang Z, Sun X. Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharmaceutica Sinica B. 2013;3:65-75.
  40. Kratzke RA, Kramer BS. Evaluation of in vitro chemosensitivity using human lung cancer cell lines. J Cell Biochem Suppl. 1996;24:160-4. PubMed PMID: 8806098.
  41. Franken NA, Rodermond HM, Stap J, Haveman J, Van Bree C. Clonogenic assay of cells in vitro. Nat Protoc. 2006;1:2315-9. doi: 10.1038/nprot.2006.339. PubMed PMID: 17406473.
  42. Buch K, Peters T, Nawroth T, Sänger M, Schmidberger H, Langguth P. Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay-A comparative study. Radiation oncology. 2012;7:1.
  43. Chou T, Martin N. CompuSyn software for drug combinations and for general dose-effect analysis and user’s guide. Paramus: ComboSyn Inc; 2007.
  44. Tartaj P, Serna CJ. Synthesis of monodisperse superparamagnetic Fe/silica nanospherical composites. J Am Chem Soc. 2003;125:15754-5.
  45. Marinin A. Synthesis and characterization of superparamagnetic iron oxide nanoparticles coated with silica. School of Information and Communication Technology Royal Institute of Technology: Stockholm; 2012.
  46. Keshavarzi E, Ghaeb Y, Rouhani SF. The magnetic properties of Fe3O4 nanoparticale with different Coats and hydrodynamic diameters. c2010. Avilable From: http://www.civilica.com/Paper-ISPTC12-ISPTC12_121.html.
  47. Wang L, Neoh K, Kang E, Shuter B, Wang SC. Superparamagnetic hyperbranched polyglycerol-grafted Fe3O4 nanoparticles as a novel magnetic resonance imaging contrast agent: an in vitro assessment. Advanced Functional Materials. 2009;19:2615-22.
  48. Ankamwar B, Lai T-C, Huang J-H, Liu R-S, Hsiao M, Chen C-H, et al. Biocompatibility of Fe3O4 nanoparticles evaluated by in vitro cytotoxicity assays using normal, glia and breast cancer cells. Nanotechnology. 2010;21:075102.
  49. Choi JY, Lee SH, Na HB, An K, Hyeon T, Seo TS. In vitro cytotoxicity screening of water-dispersible metal oxide nanoparticles in human cell lines. Bioprocess Biosyst Eng. 2010;33:21-30. doi: 10.1007/s00449-009-0354-5. PubMed PMID: 19636592.
  50. Mahmoudi M, Hofmann H, Rothen-Rutishauser B, Petri-Fink A. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem Rev. 2012;112:2323-38. doi: 10.1021/cr2002596. PubMed PMID: 22216932.
  51. Harvey KA, Xu Z, Saaddatzadeh MR, Wang H, Pollok K, Cohen-Gadol AA, et al. Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines. J Neurosurg. 2015;122:547-56. doi: 10.3171/2014.10.JNS14759. PubMed PMID: 25526274.
  52. Sutradhar KB, Amin ML. Nanotechnology in cancer drug delivery and selective targeting. ISRN Nanotechnology. 2014;2014.
  53. Saatchi K, Gelder N, Gershkovich P, Sivak O, Wasan KM, Kainthan RK, et al. Long-circulating non-toxic blood pool imaging agent based on hyperbranched polyglycerols. Int J Pharm. 2012;422:418-27. doi: 10.1016/j.ijpharm.2011.10.036. PubMed PMID: 22044540.
  54. Tubiana M, Introduction to radiobiology. Florida: CRC Press; 2005.
  55. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. Philadelphia: Lippincott Williams & Wilkins; 2006.
  56. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12:913-22. doi: 10.1007/s10495-007-0756-2. PubMed PMID: 17453160.
  57. Jia HY, Liu Y, Zhang XJ, Han L, Du LB, Tian Q, et al. Potential oxidative stress of gold nanoparticles by induced-NO releasing in serum. J Am Chem Soc. 2009;131:40-1. doi: 10.1021/ja808033w. PubMed PMID: 1907265.
  58. Klein S, Dell’Arciprete ML, Wegmann M, Distel LV, Neuhuber W, Gonzalez MC, et al. Oxidized silicon nanoparticles for radiosensitization of cancer and tissue cells. Biochem Biophys Res Commun. 2013;434:217-22. doi: 10.1016/j.bbrc.2013.03.042. PubMed PMID: 23535374.
  59. Misawa M, Takahashi J. Generation of reactive oxygen species induced by gold nanoparticles under x-ray and UV Irradiations. Nanomedicine. 2011;7:604-14. doi: 10.1016/j.nano.2011.01.014. PubMed PMID: 21333754.
  60. Gara PMD, Garabano NI, Portoles MJL, Moreno MS, Dodat D, Casas OR, et al. ROS enhancement by silicon nanoparticles in X-ray irradiated aqueous suspensions and in glioma C6 cells. J Nanopart Res. 2012;14:741.
  61. Lehnert S. Radiosensitizers and Radiochemotherapy in the Treatment of Cancer. New York: CRC Press; 2014.