Journal of Materials Science

, Volume 52, Issue 16, pp 9249–9261 | Cite as

Superparamagnetic nanohybrids with cross-linked polymers providing higher in vitro stability

  • Weerakanya ManeeprakornEmail author
  • Lionel Maurizi
  • Hathainan Siriket
  • Tuksadon Wutikhun
  • Tararaj Dharakul
  • Heinrich Hofmann


A simple, rapid, reproducible, and scalable method for generating highly stable cross-linked superparamagnetic nanohybrids was developed. Pre-coating of superparamagnetic iron oxide nanoparticle surfaces with a biocompatible polymer, hydroxy polyvinyl alcohol (PVA-OH) prior to cross-linking with silica precursor resulted in improved stability, uniform morphologies and allows for further surface functionalization. The obtained magnetic nanohybrids contain a non-porous silica layer, are monodisperse (size 50.0 ± 3.7 nm), and show colloidal stability applicable for biomedical applications (pH 7.35–7.45) with long shelf life (>9 months). In vitro studies indicate that as-prepared nanohybrids are non-cytotoxic and highly robust toward endosomal/lysosomal conditions, with no particle dissolution evident for up to 42 days. As a demonstration of the potential utility of these nanohybrids in medical diagnostic applications (e.g., MRI), surface functionalization with folic acid resulted in particle recognition and affinity to folate receptor-positive cervix (HeLa) cells. Accordingly, the facile development of these non-toxic, stable cross-linked magnetic nanohybrids, with the added benefit of scalable preparation, should serve as an entry point for the further development of safer, target specific, MRI contrast agents for cancer diagnosis.


Prussian Blue Colloidal Stability Silica Layer Silica Coating Cell Index 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to acknowledge financial support from the National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Thailand, the Swiss National Science Foundation (SNSF), the Laboratory of Powder Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), and the Faculty of Medicine Siriraj Hospital, Mahidol University.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10853_2017_1098_MOESM1_ESM.docx (3.8 mb)
Supplementary material 1 (DOCX 3922 kb)


  1. 1.
    Mahmoudi M, Hosseinkhani H, Hosseinkhani M, Boutry S, Simchi A, Journeay WS, Subramani K, Laurent S (2011) Magnetic resonance imaging tracking of stem cells in vivo using iron oxide nanoparticles as a tool for the advancement of clinical regenerative medicine. Chem Rev 111:253–280CrossRefGoogle Scholar
  2. 2.
    Mahmoudi M, Serpooshan V, Laurent S (2011) Engineered nanoparticles for biomolecular imaging. Nanoscale 3:3007–3026CrossRefGoogle Scholar
  3. 3.
    Peacock AK, Cauët SI, Taylor A, Murray P, Williams SR, Weaver JVM, Adams DJ, Rosseinsky MJ (2012) Poly[2-(methacroyloxy)ethylphosphorylcholine]-coated iron oxide nanoparticles: synthesis, colloidal stability and evaluation for stem cell labelling. Chem Commun 48:9373–9375CrossRefGoogle Scholar
  4. 4.
    Babič M, Horák D, Trchová M, Jendelová P, Glogarová KI, Lesný P, Herynek V, Hájek M, Syková E (2008) Poly(l-lysine)-modified iron oxide nanoparticles for stem cell labeling. Bioconjugate Chem 19:740–750CrossRefGoogle Scholar
  5. 5.
    Hayashi K, Ono K, Suzuki H, Sawada M, Moriya M, Sakamoto W, Yogo T (2010) High-frequency, magnetic-field-responsive drug release from magnetic nanoparticle/organic hybrid based on hyperthermic effect. ACS Appl Mater Interfaces 2:1903–1911CrossRefGoogle Scholar
  6. 6.
    Singh A, Dilnawaz F, Mewar S, Sharma U, Jagannathan NR, Sahoo SK (2011) Composite polymeric magnetic nanoparticles for co-delivery of hydrophobic and hydrophilic anticancer drugs and MRI imaging for cancer therapy. ACS Appl Mater Interfaces 3:842–856CrossRefGoogle Scholar
  7. 7.
    Liao Z, Wang H, Lv R, Zhao P, Sun X, Wang S, Su W, Niu R, Chang J (2011) Polymeric liposomes-coated superparamagnetic iron oxide nanoparticles as contrast agent for targeted magnetic resonance imaging of cancer cells. Langmuir 27:3100–3105CrossRefGoogle Scholar
  8. 8.
    Tong S, Hou S, Zheng Z, Zhou J, Bao G (2010) Coating optimization of superparamagnetic iron oxide nanoparticles for high T2 relaxivity. Nano Lett 10:4607–4613CrossRefGoogle Scholar
  9. 9.
    Sadeghiani N, Barbosa LS, Silva LP, Azevedo RB, Morais PC, Lacava ZGM (2005) Genotoxicity and inflammatory investigation in mice treated with magnetite nanoparticles surface coated with polyaspartic acid. J Magn Magn Mater 289:466–468CrossRefGoogle Scholar
  10. 10.
    Wang XY, Hussain SM, Krestin GP (2001) Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. Eur Radiol 11:2319–2331CrossRefGoogle Scholar
  11. 11.
    Wu W, He Q, Jiang C (2008) Magnetic iron oxide nanoparticles: synthesis and surface functionalization strategies. Nanoscale Res Lett 3:397–415CrossRefGoogle Scholar
  12. 12.
    Arbab AS, Wilson LB, Ashari P, Jordan EK, Lewis BK, Frank JA (2005) A model of lysosomal metabolism of dextran coated superparamagnetic iron oxide (SPIO) nanoparticles: implications for cellular magnetic resonance imaging. NMR Biomed 18:383–389CrossRefGoogle Scholar
  13. 13.
    Hradil J, Pisarev A, Babič M, Horák D (2007) Dextran-modified iron oxide nanoparticles. China Particuology 5:162–168CrossRefGoogle Scholar
  14. 14.
    Molday RS (1984) Magnetic iron-dextran microspheres, U.S. Patent 4,452,773Google Scholar
  15. 15.
    Kang HW, Josephson L, Petrovsky A, Weissleder R, Bogdanov AJ (2002) Magnetic resonance imaging of inducible E-selectin expression in human endothelial cell culture. Bioconjugate Chem 13:122–127CrossRefGoogle Scholar
  16. 16.
    Larsen EKU, Nielsen T, Wittenborn T, Birkedal H, Vorup-Jensen T, Jakobsen MH, Østergaard L, Horsman MR, Besenbacher F, Howard KA, Kjems J (2009) Size-dependent accumulation of PEGylated silane-coated magnetic iron oxide nanoparticles in murine tumors. ACS Nano 3:1947–1951CrossRefGoogle Scholar
  17. 17.
    Saifer MGP, Williams LD, Sobczyk MA, Michaels SJ, Sherman MR (2014) Selectivity of binding of PEGs and PEG-like oligomers to anti-PEG antibodies induced by methoxyPEG-proteins. Mol Immunol 57:236–246CrossRefGoogle Scholar
  18. 18.
    Valdes-Solıs T, Rebolledo AF, Sevilla M, Valle-Vigon P, Bomatí-Miguel O, Fuertes AB, Tartaj P (2009) Preparation, characterization, and enzyme immobilization capacities of superparamagnetic silica/iron oxide nanocomposites with mesostructured porosity. Chem Mater 21:1806–1814CrossRefGoogle Scholar
  19. 19.
    Strehl C, Gaber T, Maurizi L, Hahne M, Rauch R, Hoff P, Häupl T, Hofmann-Amtenbrink M, Poole AR, Hofmann H, Buttgereit F (2015) Effects of PVA coated nanoparticles on human immune cells. Int J Nanomed 10:3429–3445CrossRefGoogle Scholar
  20. 20.
    Bee A, Massart R, Neveu S (1995) Synthesis of very fine maghemite particles. J Magn Magn Mater 149:6–9CrossRefGoogle Scholar
  21. 21.
    Mahmoudi M, Simchi A, Imani M (2009) Cytotoxicity of uncoated and polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles. J Phys Chem C 113:9573–9580CrossRefGoogle Scholar
  22. 22.
    Zhou L, He B, Zhang F (2012) Facile one-pot synthesis of iron oxide nanoparticles cross-linked magnetic poly(vinyl alcohol) gel beads for drug delivery. ACS Appl Mater Interfaces 4:192–199CrossRefGoogle Scholar
  23. 23.
    Schulze F, Dienelt A, Geissler S, Zaslansky P, Schoon J, Henzler K, Guttmann P, Gramoun A, Crowe LA, Maurizi L, Vallée JP, Hofmann H, Duda GN, Ode A (2014) Amino-polyvinyl alcohol coated superparamagnetic iron oxide nanoparticles are suitable for monitoring of human mesenchymal stromal cells in vivo. Small 10:4340–4351Google Scholar
  24. 24.
    Schulze F, Gramoun A, Crowe LA, Dienelt A, Akcan T, Hofmann H, Vallée JP, Duda GN, Ode A (2015) Accumulation of amino-polyvinyl alcohol-coated superparamagnetic iron oxide nanoparticles in bone marrow: implications for local stromal cells. Nanomedicine 10:2139–2151CrossRefGoogle Scholar
  25. 25.
    Ahmad T, Bae H, Rhee I, Chang Y, Lee J, Hong S (2012) Particle size dependence of relaxivity for silica-coated iron oxide nanoparticles. Curr Appl Phys 12:969–974CrossRefGoogle Scholar
  26. 26.
    Kralj S, Makovec D, Čampelj S, Drofenik M (2009) Producing ultra-thin silica coatings on iron-oxide nanoparticles to improve their surface reactivity. J Magn Magn Mater 322:1847–1853CrossRefGoogle Scholar
  27. 27.
    Liu Q, Finch JA, Egerton R (1998) A novel two-step silica-coating process for engineering magnetic nanocomposites. Chem Mater 10:3936–3940CrossRefGoogle Scholar
  28. 28.
    Hui C, Shen C, Tian J, Bao L, Ding H, Li C, Tian Y, Shi X, Gao HT (2011) Core-shell Fe3O4@SiO2 nanoparticles synthesized with well-dispersed hydrophilic Fe3O4 seeds. Nanoscale 3:701–705CrossRefGoogle Scholar
  29. 29.
    Roca AG, Carmona D, Miguel-Sancho N, Bomati-Miguel O, Balas F, Piquer C, Santamaría J (2012) Surface functionalization for tailoring the aggregation and magnetic behaviour of silica-coated iron oxide nanostructures. Nanotechnology 23:155603CrossRefGoogle Scholar
  30. 30.
    Iqbal MS, Ma X, Chen T, Zhang L, Ren W, Xiang L, Wu A (2015) Silica-coated super-paramagnetic iron oxide nanoparticles (SPIONPs): a new type contrast agent of T1 magnetic resonance imaging (MRI). J Mater Chem B 3:5172–5181CrossRefGoogle Scholar
  31. 31.
    Ding HL, Zhang XY, Wang S, Xu JM, Su SC, Li GH (2012) Fe3O4@SiO2 core/shell nanoparticles: the silica coating regulations with a single core for different core sizes and shell thicknesses. Chem Mater 24:4572–4580CrossRefGoogle Scholar
  32. 32.
    Tartaj P, González-Carreño T, Serna CJ (2001) Single-step nanoengineering of silica coated maghemite hollow spheres with tunable magnetic properties. Adv Mater 13:1620–1624CrossRefGoogle Scholar
  33. 33.
    Barnakov YA, Yu MH, Rosenzweig Z (2005) Manipulation of the magnetic properties of magnetite-silica nanocomposite materials by controlled Stöber synthesis. Langmuir 21:7524–7527CrossRefGoogle Scholar
  34. 34.
    Singh N, Jenkins GJS, Asadi R, Doak SH (2010) Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Reviews. doi: 10.3402/nano.v1i0.5358 Google Scholar
  35. 35.
    Maurizi L, Sakulkhu U, Crowe LA, Dao VM, Leclaire N, Vallée JP, Hofmann H (2014) Syntheses of cross-linked polymeric superparamagnetic beads with tunable properties. RSC Adv 4:11142–11146CrossRefGoogle Scholar
  36. 36.
    Maurizi L, Claveau A, Hofmann H (2015) Polymer adsorption on iron oxide nanoparticles for one-step amino-functionalized silica encapsulation. J Nanomater. doi: 10.1155/2015/732719 Google Scholar
  37. 37.
    Chastellain M, Petri A, Hofmann H (2004) Particle size investigations of a multistep synthesis of PVA coated superparamagnetic nanoparticles. J Colloid Interface Sci 278:353–360CrossRefGoogle Scholar
  38. 38.
    Sonvico F, Mornet S, Vasseur S, Dubernet C, Jaillard D, Degrouard J, Hoebeke J, Duguet E, Colombo P, Couvreur P (2005) Folate-conjugated iron oxide nanoparticles for solid tumor targeting as potential specific magnetic hyperthermia mediators: synthesis, physicochemical characterization, and in vitro experiments. Bioconjug Chem 16:1181–1188CrossRefGoogle Scholar
  39. 39.
    Yang R, An Y, Miao F, Li M, Liu P, Tang Q (2014) Preparation of folic acid-conjugated, doxorubicin-loaded, magnetic bovine serum albumin nanospheres and their antitumor effects in vitro and in vivo. Int J Nanomedicine 9:4231–4243CrossRefGoogle Scholar
  40. 40.
    Pan T, Khare S, Ackah F, Huang B, Zhang W, Gabos S, Jin C, Stampfl M (2013) In vitro cytotoxicity assessment based on KC 50 with real-time cell analyzer (RTCA) assay. Comput Biol Chem 47:113–120CrossRefGoogle Scholar
  41. 41.
    Benachour H, Bastogne T, Toussaint M, Chemli Y, Sève A, Frochot C, Lux F, Tillement O, Vanderesse R, Barberi-Heyob M (2012) Real-time monitoring of photocytotoxicity in nanoparticles-based photodynamic therapy: a model-based approach. PLoS ONE 7:e48617CrossRefGoogle Scholar
  42. 42.
    Teng Z, Kuang X, Wang J, Zhang X (2013) Real-time cell analysis—a new method for dynamic, quantitative measurement of infectious viruses and antiserum neutralizing activity. J Virol Methods 193:364–370CrossRefGoogle Scholar
  43. 43.
    Otero-González L, Sierra-Alvarez R, Boitana S, Field JA (2012) Application and validation of an impedance-based real time cell analyzer to measure the toxicity of nanoparticles impacting human bronchial epithelial cells. Environ Sci Technol 46:10271–10278Google Scholar
  44. 44.
    Skotland T, Sontum PC, Oulie I (2002) In vitro stability analyses as a model for metabolism of ferromagnetic particles (Clariscan.), a contrast agent for magnetic resonance imaging. J Pharm Biomed 28:323–329CrossRefGoogle Scholar
  45. 45.
    Lévy M, Lagarde F, Maraloiu V, Blanchin M, Gendron F, Wilhelm C, Gazeau F (2010) Degradability of superparamagnetic nanoparticles in a model of intracellular environment: follow-up of magnetic, structural and chemical properties. Nanotechnology 21:395103CrossRefGoogle Scholar
  46. 46.
    Malvindi MA, Matteis VD, Galeone A, Brunetti V, Anyfantis GC, Athanassiou A, Cingolani R, Pompa PP (2014) Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. PLoS ONE 9:e85835CrossRefGoogle Scholar
  47. 47.
    Majd MH, Asgari D, Barar J, Valizadeh H, Kafil V, Coukos G, Omidi Y (2013) Specific targeting of cancer cells by multifunctional mitoxantrone-conjugated magnetic nanoparticles. J Drug Target 21:328–340CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.National Nanotechnology Center (NANOTEC)National Science and Technology Development Agency (NSTDA)PathumthaniThailand
  2. 2.Laboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303, CNRSUniversité Bourgogne Franche-ComtéDijon CedexFrance
  3. 3.Department of Immunology, Faculty of Medicine Siriraj HospitalMahidol UniversityBangkokThailand
  4. 4.Powder Technology LaboratoryEcole Polytechnique Fédérale de Lausanne (EPFL)LausanneSwitzerland

Personalised recommendations