Lomustine Loaded Superparamagnetic Iron Oxide Nanoparticles Conjugated with Folic Acid for Treatment of Glioblastoma Multiforma (GBM)

Document Type : Research article

Authors

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

2 Department of Medical Physics, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

3 Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran.

Abstract

This study aimed to improve delivery of lomustine as a chemotherapeutic agent and to increase its uptake by U87-MG cancer cells via synthesizes LN-FA-PG-SPIONs (lomustine loaded polyglycerol coated superparamagnetic iron oxide nanoparticles conjugated with folic acid). Nanoparticles were synthesized by thermal decomposition method and characterized using TEM (transmission microscope), FTIR (Fourier transform infrared spectroscopy), and VSM (vibrating sample magnetometer). Lomustine release from nanoparticles was determined by dialysis-bag diffusion technique. Nanoparticles cytotoxicity was evaluated by MTT assay. Mean size of SPIONs and FA-PG-SPIONs (PG-SPIONs conjugated with folic acid) were 7.1 ± 1.13 nm and 25.1 ± 3.94 nm, respectively. Based on FTIR spectra SPIONs were successfully coated by polyglycerol and conjugated with folic acid. Lomustine encapsulation efficiency was 46 ± 6.8 %. SPIONs were cytotoxic on U87-MG cells at concentration above 100 ug/ml (p <0.05) but PG-SPIONs do not reduce viability significantly (p > 0.05). Conjugation of folic acid with PG-SPIONs increased nanoparticles uptake by U87-MG cells (p < 0.05). We concluded that however FA-PG-SPIONs are proposed as a useful tracer for diagnostic and treatment of GBM but their drug delivery properties for lomustine is not satisfactory and more researches are necessary with this regard.

Graphical Abstract

Lomustine Loaded Superparamagnetic Iron Oxide Nanoparticles Conjugated with Folic Acid for Treatment of Glioblastoma Multiforma (GBM)

Keywords

Main Subjects


  1. Brat DJ, Prayson RA, Ryken TC, et al. Diagnosis of malignant glioma: role of neuropathology. Journal of neuro-oncology. 2008;89(3):287-311.
  2. Wen PY, Kesari S. Malignant gliomas in adults. New England Journal of Medicine. 2008;359(5):492-507.
  3. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro-oncology. 2014;16(suppl 4):iv1-iv63.
  4. Fang C, Wang K, Stephen ZR, et al. Temozolomide nanoparticles for targeted glioblastoma therapy. ACS applied materials & interfaces. 2015;7(12):6674-6682.
  5. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807-1812.
  6. Huse JT, Holland E, DeAngelis LM. Glioblastoma: molecular analysis and clinical implications. Annual review of medicine. 2013;64:59-70.
  7. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. Jama. 2013;310(17):1842-1850.
  8. Mehrotra A, Nagarwal RC, Pandit JK. Lomustine loaded chitosan nanoparticles: characterization and in-vitro cytotoxicity on human lung cancer cell line L132. Chemical and Pharmaceutical Bulletin. 2011;59(3):315-320.
  9. Mehrotra A, Pandit JK. Critical process parameters evaluation of modified nanoprecipitation method on lomustine nanoparticles and cytostatic activity study on L132 human cancer cell line. Journal of Nanomedicine & Nanotechnology. 2013;2012.
  10. Harvey KA, Xu Z, Saaddatzadeh MR, et al. Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines. Journal of neurosurgery. 2015;122(3):547-556.
  11. Allen TM, Cullis PR. Drug delivery systems: entering the mainstream. Science. 2004;303(5665):1818-1822.
  12. Davis ME, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature reviews Drug discovery. 2008;7(9):771-782.
  13. Singh R, Lillard JW. Nanoparticle-based targeted drug delivery. Experimental and molecular pathology. 2009;86(3):215-223.
  14. Pankhurst QA, Connolly J, Jones SK, et al. Applications of magnetic nanoparticles in biomedicine. Journal of physics D: Applied physics. 2003;36(13):R167.
  15. Chertok B, Moffat BA, David AE, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials. 2008;29(4):487-496.
  16. Hadjipanayis CG, Machaidze R, Kaluzova M, et al. EGFRvIII antibody–conjugated iron oxide nanoparticles for magnetic resonance imaging–guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer research. 2010;70(15):6303-6312.
  17. Mahmoudi M, Sant S, Wang B, et al. Superparamagnetic iron oxide nanoparticles (SPIONs): development, surface modification and applications in chemotherapy. Advanced drug delivery reviews. 2011;63(1):24-46.
  18. Garin-Chesa P, Campbell I, Saigo P, et al. Trophoblast and ovarian cancer antigen LK26. Sensitivity and specificity in immunopathology and molecular identification as a folate-binding protein. The American journal of pathology. 1993;142(2):557.
  19. Parker N, Turk MJ, Westrick E, et al. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Analytical biochemistry. 2005;338(2):284-293.
  20. Reddy JA, Low PS. Folate-mediated targeting of therapeutic and imaging agents to cancers. Critical Reviews™ in Therapeutic Drug Carrier Systems. 1998;15(6).
  21. Zhang Y, Sun C, Kohler N, et al. Self-assembled coatings on individual monodisperse magnetite nanoparticles for efficient intracellular uptake. Biomedical microdevices. 2004;6(1):33-40.
  22. Veiseh O, Sun C, Gunn J, et al. Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano letters. 2005;5(6):1003-1008.
  23. Hu F, Neoh KG, Cen L, et al. Cellular response to magnetic nanoparticles “PEGylated” via surface-initiated atom transfer radical polymerization. Biomacromolecules. 2006;7(3):809-816.
  24. Lutz J-F, Stiller S, Hoth A, et al. One-pot synthesis of PEGylated ultrasmall iron-oxide nanoparticles and their in vivo evaluation as magnetic resonance imaging contrast agents. Biomacromolecules. 2006;7(11):3132-3138.
  25. Frey H. Hyperbranched Polyglycerols (Synthesis and Applications). Encyclopedia of Polymeric Nanomaterials. 2015:977-980.
  26. Saucier-Sawyer JK, Deng Y, Seo Y-E, et al. Systemic delivery of blood–brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue. Journal of drug targeting. 2015;23(7-8):736-749.
  27. Deng Y, Saucier-Sawyer JK, Hoimes CJ, et al. The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles. Biomaterials. 2014;35(24):6595-6602.
  28. Maity D, Choo S-G, Yi J, et al. Synthesis of magnetite nanoparticles via a solvent-free thermal decomposition route. Journal of Magnetism and Magnetic Materials. 2009;321(9):1256-1259.
  29. Zhao L, Chano T, Morikawa 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(24):5107-5117.
  30. Faraji AH, Wipf P. Nanoparticles in cellular drug delivery. Bioorganic & medicinal chemistry. 2009;17(8):2950-2962.
  31. Lu AH, Salabas EeL, Schüth F. Magnetic nanoparticles: synthesis, protection, functionalization, and application. Angewandte Chemie International Edition. 2007;46(8):1222-1244.
  32. Tartaj P, Serna CJ. Synthesis of monodisperse superparamagnetic Fe/silica nanospherical composites. Journal of the American Chemical Society. 2003;125(51):15754-15755.
  33. Huang F-K, Chen W-C, Lai S-F, et al. Enhancement of irradiation effects on cancer cells by cross-linked dextran-coated iron oxide (CLIO) nanoparticles. Physics in medicine and biology. 2009;55(2):469.
  34. Marinin A. Synthesis and characterization of superparamagnetic iron oxide nanoparticles coated with silica. 2012.
  35. Keshavarzi, Ezat; Yosef GHaeb & Seyede Fereshte Rouhani, 2010, The magnetic properties of Fe3O4 nanoparticale with different Coats and hydrodynamic diameters, http://www.civilica.com/Paper-ISPTC12-ISPTC12_121.html.
  36. Wang L, Neoh K, Kang E, et al. Superparamagnetic Hyperbranched Polyglycerol‐Grafted Fe3O4 Nanoparticles as a Novel Magnetic Resonance Imaging Contrast Agent: An In Vitro Assessment. Advanced Functional Materials. 2009;19(16):2615-2622.
  37. Mohapatra S, Mallick S, Maiti T, et al. Synthesis of highly stable folic acid conjugated magnetite nanoparticles for targeting cancer cells. Nanotechnology. 2007;18(38):385102.
  38. Chen J, Li S, Shen Q, et al. Enhanced cellular uptake of folic acid–conjugated PLGA–PEG nanoparticles loaded with vincristine sulfate in human breast cancer. Drug development and industrial pharmacy. 2011;37(11):1339-1346.
  39. Ankamwar B, Lai T, Huang J, et al. Biocompatibility of Fe3O4 nanoparticles evaluated by in vitro cytotoxicity assays using normal, glia and breast cancer cells. Nanotechnology. 2010;21(7):075102.
  40. Choi JY, Lee SH, Na HB, et al. In vitro cytotoxicity screening of water-dispersible metal oxide nanoparticles in human cell lines. Bioprocess and biosystems engineering. 2010;33(1):21-30.
  41. Mahmoudi M, Hofmann H, Rothen-Rutishauser B, et al. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chemical reviews. 2011;112(4):2323-2338.
  42. Sutradhar KB, Amin ML. Nanotechnology in cancer drug delivery and selective targeting. ISRN Nanotechnology. 2014;2014.
  43. Saatchi K, Gelder N, Gershkovich P, et al. Long-circulating non-toxic blood pool imaging agent based on hyperbranched polyglycerols. International journal of pharmaceutics. 2012;422(1):418-427.
  44. Huang Y, Mao K, Zhang B, et al. Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics. Materials Science and Engineering: C. 2017;70:763-771.