Ex vivo assessment of polyol coated-iron oxide nanoparticles for MRI diagnosis applications: toxicological and MRI contrast enhancement effects

  • Oscar Bomati-Miguel
  • Nuria Miguel-Sancho
  • Ibane Abasolo
  • Ana Paula Candiota
  • Alejandro G. Roca
  • Milena Acosta
  • Simó SchwartzJr.
  • Carles Arus
  • Clara Marquina
  • Gema Martinez
  • Jesus Santamaria
Research Paper

Abstract

Polyol synthesis is a promising method to obtain directly pharmaceutical grade colloidal dispersion of superparamagnetic iron oxide nanoparticles (SPIONs). Here, we study the biocompatibility and performance as T2-MRI contrast agents (CAs) of high quality magnetic colloidal dispersions (average hydrodynamic aggregate diameter of 16-27 nm) consisting of polyol-synthesized SPIONs (5 nm in mean particle size) coated with triethylene glycol (TEG) chains (TEG-SPIONs), which were subsequently functionalized to carboxyl-terminated meso-2-3-dimercaptosuccinic acid (DMSA) coated-iron oxide nanoparticles (DMSA-SPIONs). Standard MTT assays on HeLa, U87MG, and HepG2 cells revealed that colloidal dispersions of TEG-coated iron oxide nanoparticles did not induce any loss of cell viability after 3 days incubation with dose concentrations below 50 μg Fe/ml. However, after these nanoparticles were functionalized with DMSA molecules, an increase on their cytotoxicity was observed, so that particles bearing free terminal carboxyl groups on their surface were not cytotoxic only at low concentrations (<10 μg Fe/ml). Moreover, cell uptake assays on HeLa and U87MG and hemolysis tests have demonstrated that TEG-SPIONs and DMSA-SPIONs were well internalized by the cells and did not induce any adverse effect on the red blood cells at the tested concentrations. Finally, in vitro relaxivity measurements and post mortem MRI studies in mice indicated that both types of coated-iron oxide nanoparticles produced higher negative T2-MRI contrast enhancement than that measured for a similar commercial T2-MRI CAs consisting in dextran-coated ultra-small iron oxide nanoparticles (Ferumoxtran-10). In conclusion, the above attributes make both types of as synthesized coated-iron oxide nanoparticles, but especially DMSA-SPIONs, promising candidates as T2-MRI CAs for nanoparticle-enhanced MRI diagnosis applications.

Keywords

Polyol-mediated synthesis Superparamagnetic iron oxide nanoparticles In vitro cytotoxicity Hemolysis tests Contrast agents for nanoparticle-enhanced magnetic resonance imaging Nanomedicine 

Supplementary material

11051_2014_2292_MOESM1_ESM.doc (9 mb)
Supplementary material 1 (DOC 9166 kb)

References

  1. Anzai Y, Blackwell KE, Hirschowitz SL, Rogers JW, Sato Y, Yuh WT, Runge VM, Morris MR, McLachlan SJ, Lufkin RB (1994) Initial clinical experience with dextran-coated superparamagnetic iron oxide for detection of lymph node metastases in patients with head and neck cancer. Radiology 192:709–715Google Scholar
  2. Bomati-Miguel O, Gossuin Y, Morales MP, Gillis P, Muller RN (2007) Comparative analysis of the 1H NMR relaxation enhancement produced by iron oxide and core–shell iron–iron oxide nanoparticles. Magn Reson Imaging 25:1437–1441CrossRefGoogle Scholar
  3. Cañete M, Soriano J, Villanueva A, Roca AG, Veintemillas S, Serna CJ, Miranda R, Morales MP (2010) The endocytic penetration mechanism of iron oxide magnetic nanoparticles with positively charged cover: a morphological approach. Int J Mol Med 26:533–539CrossRefGoogle Scholar
  4. Caravan P (2009) Protein-targeted gadolinium-based magnetic resonance imaging (MRI) contrast agents: design and mechanism of action. Acc Chem Res 42:851–862CrossRefGoogle Scholar
  5. Coleman J, Nascimiento R, Solomon SB (2007) Advances in imaging for urologic procedures. Nat Clin Pract Urol 4:498–504CrossRefGoogle Scholar
  6. Corot C, Robert P, Idée JM, Port M (2006) Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58(14):1471–1504CrossRefGoogle Scholar
  7. Figuerola A, Di Corato R, Manna L, Pellegrino T (2010) From iron oxide nanoparticles towards advanced iron-based inorganic materials designed for biomedical applications. Pharm Res 62(2):126–143CrossRefGoogle Scholar
  8. Fröhlich E (2012) The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. Int J Nanomedicine 7:5577–5591CrossRefGoogle Scholar
  9. Gossuin Y, Gillis P, Hocq A, Vuong Q, Roch A (2009) Magnetic resonance relaxation properties of superparamagnetic particles. Wires Nanomed Nanobiotechnol 1(3):299–310CrossRefGoogle Scholar
  10. Groman EV, Bouchard JC, Reinhardt CP, Vaccaro DE (2007) Ultrasmall mixed ferrite colloids as multidimensional magnetic resonance imaging, cell labeling, and cell sorting agents. Bioconjug Chem 18:1763–1771CrossRefGoogle Scholar
  11. Gupta AK, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26(18):3995–4021CrossRefGoogle Scholar
  12. Hahn MA, Singh AK, Sharma P, Brown SC, Moudgil BM (2011) Nanoparticles as contrast agents for in vivo bioimaging: current status and future perspectives. Anal Bioanal Chem 399:3–27CrossRefGoogle Scholar
  13. Harisinghani MG, Saini S, Weissleder R, Hahn PF, Yantiss RK, Tempany C, Wood BJ, Mueller PR (1999) MR lymphangiography using ultrasmall superparamagnetic iron oxide in patients with primary abdominal and pelvic malignancies: radiographic–pathologic correlation. AJR Am J Roentgenol 172:1347–1351CrossRefGoogle Scholar
  14. Huang J, Zhong X, Wang L, Yang L, Mao H (2012) Improving the magnetic resonance imaging contrast and detection methods with engineered magnetic nanoparticles. Theranostics 2(1):86–102CrossRefGoogle Scholar
  15. Jung CW, Jacobs P (1995) Physical and chemical properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Mag Reson Imaging 13(5):661–674CrossRefGoogle Scholar
  16. Kehagias DT, Gouliamos AD, Smyrniotis V, Vlahos LJ (2001) Diagnostic efficacy and safety of MRI of the liver with superparamagnetic iron oxide particles (SH U 555 A). J Magn Reson Imaging 14:595–601CrossRefGoogle Scholar
  17. Kriege M et al (2004) Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351:427–437CrossRefGoogle Scholar
  18. Laurent S, Forge D, Port M, Roch A, Robic C, Vander Elst L, Muller RN (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev 108:2064–2110CrossRefGoogle Scholar
  19. Maity D, Kale SN, Kaul-Ghanekar R, Xue JM, Ding J (2009) Studies of magnetite nanoparticles synthesized by thermal decomposition of iron(III) acetylacetonate in tri(ethyleneglycol). J Magn Magn Mater 321:3093–3098CrossRefGoogle Scholar
  20. Maity D, Chandrasekharan P, Yang CT, Chuang KH, Shuter B, Xue JM, Ding J, Feng SS (2010) Facile synthesis of water-stable magnetite nanoparticles for clinical MRI and magnetic hyperthermia applications. Nanomedicine 5(10):1571–1584CrossRefGoogle Scholar
  21. McDermott S, Guimaraes AR (2012) Magnetic nanoparticles in the imaging of tumor angiogenesis. Appl Sci 2(2):525–534CrossRefGoogle Scholar
  22. Miguel-Sancho M, Bomati-Miguel O, Colom G, Pablo-Salvador J, Marco MP, Santamaría J (2011) Development of stable, water-dispersable, and biofunctionalizable superparamagnetic iron oxide nanoparticles. Chem Mater 23:2795–2802CrossRefGoogle Scholar
  23. Miguel-Sancho M, Bomatí-Miguel O, Roca AG, Martínez G, Arruebo M, Santamaría J (2012) Synthesis of magnetic nanocrystals by thermal decomposition in glycol media: effect of process variables and mechanistic study. Ind Eng Chem Res 51:8348–8357CrossRefGoogle Scholar
  24. Mondini S, Cenedese S, Marioni G, Molteni G, Santo N, Bianchi CL, Ponti A (2008) One-step synthesis and functionalization of hydroxyl-decorated magnetite nanoparticles. J Colloid Interface Sci 322:173CrossRefGoogle Scholar
  25. Monet X, Weissleder R, Josephson L (2006) Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas. Bioconjug Chem 17(4):905–911CrossRefGoogle Scholar
  26. Morales MP, Bomati-Miguel O, Perez de Alejo R, Ruiz-Cabello J, Veintemillas-Verdaguer S, O’Grady K (2003) Contrast agents for MRI based on iron oxide nanoparticles prepared by laser pyrolysis. J Magn Magn Mater 266:102–109CrossRefGoogle Scholar
  27. Pankhurst QA, Thanh NKT, Jones SK, Dobson J (2009) Progress in applications of magnetic nanoparticles in biomedicine. J Phys D 42:224001CrossRefGoogle Scholar
  28. Roca AG, Veintemillas-Verdaguer S, Port M, Robic C, Serna CJ, Morales MP (2009) Effect of nanoparticle and aggregate size on the relaxometric properties of MR contrast agents based on high quality magnetite nanoparticles. J Phys Chem B 113:7033–7039CrossRefGoogle Scholar
  29. Roca AG, Carmona D, Miguel-Sancho N, Bomati-Miguel O, Balas F, Piquer C, Santamaria J (2012) Surface functionalization for tailoring the aggregation and magnetic behaviour of silica-coated iron oxide nanostructures. Nanotechnology 23:155603CrossRefGoogle Scholar
  30. Rümenapp C, Gleich B, Haase A (2012) Magnetic nanoparticles in magnetic resonance imaging and diagnostics. Pharm Res 29(5):1165–1179CrossRefGoogle Scholar
  31. Sharma P, Brown S, Walter G, Santra S, Moudgil B (2006) Nanoparticles for bioimaging. Adv Colloid Interface Sci 123–126:471–485CrossRefGoogle Scholar
  32. Shen T, Weissleder R, Papisov M, Bogdanov A Jr, Brady TJ (1993) Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 29(5):599–604CrossRefGoogle Scholar
  33. Sun C, Sze R, Zhang M (2006) Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI. J Biomed Mater Res A 78(3):550–557CrossRefGoogle Scholar
  34. Suzuki H, Tsurita G, Ishihara S, Akahane M, Kitayama J, Nagawa H (2008) Resovist-enhanced MRI for preoperative assessment of colorectal hepatic metastases: a case of multiple bile duct hamartomas associated with colon cancer. Case Rep Gastroenterol 2(3):509–516CrossRefGoogle Scholar
  35. Theppaleak T, Tumcharern G, Wichai U, Rutnakornpituk M (2009) Synthesis of water dispersible magnetite nanoparticles in the presence of hydrophilic polymers. Polym Bull 63:79–90CrossRefGoogle Scholar
  36. Thorek DLJ, Chen AK, Czupryna J, Tsourkas A (2006) Superparamagnetic iron oxide nanoparticle probes for molecular imaging. Ann Biomed Eng 34(1):23–28CrossRefGoogle Scholar
  37. Troprès I, Grimault S, Vaeth A, Grillon E, Julien C, Payen JF, Lamalle L, Décorps M (2001) Vessel size imaging. Magn Reson Med 45:397–408CrossRefGoogle Scholar
  38. Villanueva A, Cañete M, Roca AG, Calero M, Veintemillas-Verdagüer S, Serna CJ, Morales MP, Miranda R (2009) The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells. Nanotechnology 20:115103 (9 pp)CrossRefGoogle Scholar
  39. Wan J, Cai W, Meng X, Liu E (2007) Monodisperse water-soluble magnetite nanoparticles prepared by polyol process for high-performance magnetic resonance imaging. Chem Commun 47:5004–5006CrossRefGoogle Scholar
  40. Wei C, Wan J (2007) Facile synthesis of superparamagnetic magnetite nanoparticles in liquid polyols. J Colloid Interface Sci 305:366–370CrossRefGoogle Scholar
  41. Weinreb JC, Abu-Alpha AK (2009) Gadolinium-based contrast agents and nephrogenic systemic fibrosis: why did it happen and what have we learned? J Magn Reson Imaging 30:1236–1239CrossRefGoogle Scholar
  42. Weissleder R, Hahn PF, Stark DD, Elizondo G, Saini S, Todd LE, Wittenberg J, Ferruci JT (1998) Superparamagnetic iron oxide: enhanced detection of splenic tumors with MR imaging. Radiology 169:399–403Google Scholar
  43. Wu W, He Q, Jiang C (2008) Magnetic iron oxide nanoparticles: synthesis and surface functionalization strategies. Nanoscale Res Lett 3:397–415CrossRefGoogle Scholar
  44. Yan GP, Robinson L, Hogg P (2007) Magnetic resonance imaging contrast agents: overview and perspectives. Radiography 13:e5–e19CrossRefGoogle Scholar
  45. Yang WJ, Lee JH, Hong SC, Lee J, Lee J, Han DW (2013) Nanoparticles with various surface-functional groups against human normal fibroblast and fibrosarcoma cells. Materials 6:4689–4706CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Oscar Bomati-Miguel
    • 1
  • Nuria Miguel-Sancho
    • 2
    • 3
  • Ibane Abasolo
    • 2
    • 4
  • Ana Paula Candiota
    • 2
    • 5
    • 6
  • Alejandro G. Roca
    • 2
    • 3
  • Milena Acosta
    • 2
    • 5
  • Simó SchwartzJr.
    • 2
    • 7
  • Carles Arus
    • 2
    • 5
    • 6
  • Clara Marquina
    • 8
    • 9
  • Gema Martinez
    • 2
    • 3
  • Jesus Santamaria
    • 2
    • 3
  1. 1.Departamento de Física Aplicada e Instituto de Ciencia de Materiales Nicolás Cabrera, Facultad de CienciasUniversidad Autónoma de MadridMadridSpain
  2. 2.Centro de Investigación Biomédica en Red – Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN)ZaragozaSpain
  3. 3.Instituto de Nanociencia de Aragón (INA)Universidad de ZaragozaZaragozaSpain
  4. 4.Functional Validation and Preclinical Research, CIBBIM-NanomedicineVall d’Hebron Institut de Recerca and Universitat Autònoma de BarcelonaBarcelonaSpain
  5. 5.Departament de Bioquímica i Biología Molecular, Unitat de Bioquímica de Biociències, Edifici CsUniversitat Autònoma de BarcelonaCerdanyola del VallèsSpain
  6. 6.Institut de Biotecnologia i de BiomedicinaUniversitat Autònoma de Barcelona08193Spain
  7. 7.Drug Delivery and Targeting, CIBBIM-NanomedicineVall d’Hebron Research Institute and Universitat Autònoma de BarcelonaBarcelonaSpain
  8. 8.Facultad de CienciasInstituto de Ciencia de Materiales de Aragón (ICMA, CSIC-Universidad de Zaragoza)ZaragozaSpain
  9. 9.Departamento de Física de la Materia Condensada, Facultad de CienciasUniversidad de ZaragozaZaragozaSpain

Personalised recommendations