Paramagnetic nanoparticles as potential MRI contrast agents: characterization, NMR relaxation, simulations and theory

  • Quoc Lam Vuong
  • Sabine Van Doorslaer
  • Jean-Luc Bridot
  • Corradina Argante
  • Gabriela Alejandro
  • Raphaël Hermann
  • Sabrina Disch
  • Carlos Mattea
  • Siegfried Stapf
  • Yves Gossuin
Research Article



Paramagnetic nanoparticles, mainly rare earth oxides and hydroxides, have been produced these last few years for use as MRI contrast agents. They could become an interesting alternative to iron oxide particles. However, their relaxation properties are not well understood.

Materials and methods

Magnetometry, 1H and 2H NMR relaxation results at different magnetic fields and electron paramagnetic resonance are used to investigate the relaxation induced by paramagnetic particles. When combined with computer simulations of transverse relaxation, they allow an accurate description of the relaxation induced by paramagnetic particles.


For gadolinium hydroxide particles, both T1 and T2 relaxation are due to a chemical exchange of protons between the particle surface and bulk water, called inner sphere relaxation. The inner sphere is also responsible for T1 relaxation of dysprosium, holmium, terbium and erbium containing particles. However, for these latter compounds, T2 relaxation is caused by water diffusion in the field inhomogeneities created by the magnetic particle, the outer-sphere relaxation mechanism. The different relaxation behaviors are caused by different electron relaxation times (estimated by electron paramagnetic resonance).


These findings may allow tailoring paramagnetic particles: ultrasmall gadolinium oxide and hydroxide particles for T1 contrast agents, with shapes ensuring the highest surface-to-volume ratio. All the other compounds present interesting T2 relaxation performance at high fields. These results are in agreement with computer simulations and theoretical predictions of the outer-sphere and static dephasing regime theories. The T2 efficiency would be optimum for spherical particles of 40–50 nm radius.


Nanoparticles Paramagnetic Contrast agents MRI Relaxation Simulation Relaxation theory 

Supplementary material

10334_2012_326_MOESM1_ESM.docx (56 kb)
Supplementary material 1 (DOCX 56 kb)


  1. 1.
    Modo MJM, Bulte JWM (2007) Molecular and cellular MR imaging. CRC Press, ClevelandCrossRefGoogle Scholar
  2. 2.
    Aime S, Cabella C, Colombatto S, Crich SG, Gianolio E, Maggioni F (2002) Insights into the use of paramagnetic Gd(III) complexes in MR-molecular imaging investigations. J Magn Reson Imaging 16:394–406PubMedCrossRefGoogle Scholar
  3. 3.
    Jung CW, Jacobs P (1995) Physical and chemical properties of Superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Magn Reson Imaging 13:661–674PubMedCrossRefGoogle Scholar
  4. 4.
    Engstrom M, Klasson A, Pedersen H, Vahlberg C, Käll PO, Uvdal K (2006) High proton relaxivity for gadolinium oxide nanoparticles. Magn Reson Mater Phy Biol Med 19:180–186CrossRefGoogle Scholar
  5. 5.
    Fortin MA, Petoral RM, Söderlind F, Klasson A, Engström M, Veres T, Käll PO, Uvdal K (2007) Polyethylene glycol-covered ultra-small Gd2O3 nanoparticles for positive contrast at 1.5 T magnetic resonance clinical scanning. Nanotechnology 18:395501CrossRefGoogle Scholar
  6. 6.
    Arrais A, Botta M, Avedano S, Giovenzana GB, Gianolio E, Boccaleri E, Stanghellini PL, Aime S (2008) Carbon coated microshells containing nanosized Gd(III) oxidic phases for multiple bio-medical applications. Chem Commun (45):5936–5938Google Scholar
  7. 7.
    Norek M, Pereira GA, Geraldes CFGC, Denkova A, Zhou W, Peters JA (2007) NMR transversal relaxivity of suspensions of lanthanide oxide nanoparticles. J Phys Chem C 111:10240–10246CrossRefGoogle Scholar
  8. 8.
    Norek M, Kampert E, Zeitler U, Peters JA (2008) Tuning of the size of DY2O3 nanoparticles for optimal performance as an MRI contrast agent. J Am Chem Soc 130:5335–5340PubMedCrossRefGoogle Scholar
  9. 9.
    Gossuin Y, Hocq A, Vuong QL, Disch S, Hermann RP, Gillis P (2008) Physico-chemical and NMR relaxometric characterization of gadolinium hydroxide and dysprosium oxide nanoparticles. Nanotechnology 19:475102PubMedCrossRefGoogle Scholar
  10. 10.
    Yin YD, Hong GY (2006) Synthesis and characterization of Gd(OH)(3) nanobundles. J Nanoparticle Res 8:755–760CrossRefGoogle Scholar
  11. 11.
    Song XC, Zheng YF, Wang Y (2008) Selected-control synthesis of dysprosium hydroxide and oxide nanorods by adjusting hydrothermal temperature. Mater Res Bull 43:1106–1111CrossRefGoogle Scholar
  12. 12.
    Zhang N, Yi R, Zhou L, Gao G, Shi R, Qiu G, Liu X (2009) Lanthanide hydroxide nanorods and their thermal decomposition to lanthanide oxide nanorods. Mater Chem Phys 114:160–167CrossRefGoogle Scholar
  13. 13.
    Happy Tok AIY, Boey FYC, Huebner R, Ng SH (2006) Synthesis of dysprosium oxide by homogeneous precipitation. J Electroceramics 17:75–78CrossRefGoogle Scholar
  14. 14.
    Happy Tok AIY, Su LT, Boey FYC, Ng SH (2007) Homogeneous precipitation of Dy2O3 nanoparticles-effects of synthesis parameters. J Nanosci Nanotechnol 7:907–915PubMedCrossRefGoogle Scholar
  15. 15.
    Soliman SA, Abu-Zied BM (2009) Thermal genesis, characterization, and electrical conductivity measurements of terbium oxide catalyst obtained from terbium acetate. Thermochim Acta 491:84–91CrossRefGoogle Scholar
  16. 16.
    Bazzi R, Flores-Gonzalez MA, Louis C, Lebbou K, Dujardin C, Brenier A, Zheng W, Tillement O, Bernstein E, Perriat P (2003) Synthesis and luminescent properties of sub-5-nm lanthanide oxides nanoparticles. J Lumin 102:445–450CrossRefGoogle Scholar
  17. 17.
    Bridot JL, Faure A-C, Dayde D, Rivière C, Le Duc G, Billotey C, Janier M, Josserand V, Coll J-L, Perriat P, Roux S, Tillement O (2009) Hybrid gadolinium oxide nanoparticles combining imaging and therapy. J Mater Chem 19:2328–2335CrossRefGoogle Scholar
  18. 18.
    Qian LW, Gui YC, Guo SA, Qiang G, Qian XF (2009) Controlled synthesis of light rare-earth hydroxide nanorods via a simple solution route. J Phys Chem Solids 70:688–693CrossRefGoogle Scholar
  19. 19.
    Jia G, You H, Liu K, Zheng Y, Guo N, Jia J, Zhang H (2010) Highly uniform YBO3 hierarchical architectures: facile synthesis and tunable luminescence properties. Chem Eur J 16:2930–2937PubMedCrossRefGoogle Scholar
  20. 20.
    Li L, Yang HK, Moon BK, Choi BC, Jeong JH, Kim KH (2010) Photoluminescent properties of Ln(2)O(3):Eu3+ (Ln = Y, Lu and Gd) prepared by hydrothermal process and sol-gel method. Mater Chem Phys 119:471–477CrossRefGoogle Scholar
  21. 21.
    Petoral RM, Söderlind F, Klasson A, Suska A, Fortin MA, Abrikossova N, Selegård L, Käll P-O, Engström M, Uvdal K (2009) Synthesis and characterization of Tb3+-doped Gd2O3 nanocrystals: a bifunctional material with combined fluorescent labeling and MRI contrast agent properties. J Phys Chem C 113:6913–6920CrossRefGoogle Scholar
  22. 22.
    Dosev D, Nichkova M, Dumas RK, Gee SJ, Hammock BD, Liu K, Kennedy IM (2007) Magnetic/luminescent core/shell particles synthesized by spray pyrolysis and their application in immunoassays with internal standard. Nanotechnology 18:055102CrossRefGoogle Scholar
  23. 23.
    Das GK, Heng BC, Ng S-C, White T, Loo JSC, D’Silva L, Padmanabhan P, Bhakoo KK, Selvan ST, Tan TTY (2010) Gadolinium oxide ultra narrow nanorods as multimodal contrast agents for optical and magnetic resonance imaging. Langmuir 26:8959–8965PubMedCrossRefGoogle Scholar
  24. 24.
    Yoon YS, Lee B-I, Lee KS, Im GH, Byeon S-H, Lee JH, Lee IS (2009) Surface modification of exfoliated layered gadolinium hydroxide for the development of multimodal contrast agents for MRI and fluorescence imaging. Adv Funct Mater 19:3375–3380CrossRefGoogle Scholar
  25. 25.
    Yoon YS, Lee B-I, Lee KS, Heo H, Lee JH, Byeon S-H, Lee IS (2010) Fabrication of a silica sphere with fluorescent and MR contrasting GdPO4 nanoparticles from layered gadolinium hydroxide. Chem Commun 46:3654–3656CrossRefGoogle Scholar
  26. 26.
    Gossuin Y, Gillis P, Hocq A, Vuong QL, Roch A (2009) MR relaxation properties of superparamagnetic particles. Wiley Interdisciplinary Reviews—Nanomed Nanobiotechnol 1:299–310CrossRefGoogle Scholar
  27. 27.
    Cullity BD, Graham CD (2008) Introduction to magnetic materials, 2nd edn. Wiley-IEEE Press, HobokenCrossRefGoogle Scholar
  28. 28.
    Klasson A, Ahrén M, Hellqvist E, Söderlind F, Rosén A, Käll P-O, Uvdal K, Engström M (2008) Positive MRI contrast enhancement in THP-1 cells with Gd2O3 nanoparticles. Contrast Media Mol Imaging 3:106–111PubMedCrossRefGoogle Scholar
  29. 29.
    Bulte JWM, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17:484–499PubMedCrossRefGoogle Scholar
  30. 30.
    Néel L (1948) Magnetic properties of ferrites: ferrimagnetism and antiferromagnetism. Ann Phys Paris 3:137–198Google Scholar
  31. 31.
    Ahrén M, Selegård L, Klasson A, Söderlind F, Abrikossova N, Skoglund C, Bengtsson T, Engström M, Käll P-O, Uvdal K (2010) Synthesis and characterization of PEGylated Gd2O3 nanoparticles for MRI contrast enhancement. Langmuir 26:5753–5762PubMedCrossRefGoogle Scholar
  32. 32.
    Cheung ENM, Alvares RDA, Oakden W, Chaudhary R, Hill ML, Pichaandi J, Mo GCH, Yip C, Macdonald PM, Stanisz GJ, van Veggel FCJM, Cheung RSP (2010) Polymer-stabilized lanthanide fluoride nanoparticle aggregates as contrast agents for magnetic resonance imaging and computed tomography. Chem Mater 22:4728–4739CrossRefGoogle Scholar
  33. 33.
    Choi ES, Park JY, Baek MJ, Xu W, Kattel K, Kim JH, Lee JJ, Chang J, Kim TJ, Bae JE, Chae KS, Suh KJ, Lee GH (2010) Water-soluble ultra-small manganese oxide surface doped gadolinium oxide (Gd2O3@MnO) nanoparticles for MRI contrast agent. Eur J Inorg Chem 28:4555–4560CrossRefGoogle Scholar
  34. 34.
    Sánchez P, Valero E, Gálvez N, Domínguez-Vera JM, Marinone M, Poletti G, Corti M, Lascialfari A (2009) MRI relaxation properties of water-soluble apoferritin-encapsulated gadolinium oxide-hydroxide nanoparticles. Dalton Trans 5:800–804PubMedCrossRefGoogle Scholar
  35. 35.
    Park JH, Baek MJ, Choi ES, Woo S, Kim JH, Kim TJ, Jung JC, Chae KS, Chang Y, Lee GH (2009) Paramagnetic ultrasmall gadolinium oxide nanoparticles as advanced T1 MRI contrast agent: account for large longitudinal relaxivity, optimal particle diameter, and in vivo T1 MR images. ACS Nano 3:3663–3669PubMedCrossRefGoogle Scholar
  36. 36.
    Deo A, Fogel M, Cowper SE (2007) Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol 2:264–267PubMedCrossRefGoogle Scholar
  37. 37.
    Stoll S, Schweiger A (2006) EasySpin, a comprehensive software package for spectral simulation and analysis in EPR. J Magn Reson 178:42–55PubMedCrossRefGoogle Scholar
  38. 38.
    Gillis P, Moiny F, Brooks RA (2002) On T2-Shortening by strongly magnetized spheres: a partial refocusing model. Magn Reson Med 47:257–263PubMedCrossRefGoogle Scholar
  39. 39.
    Vuong QL, Gillis P, Gossuin Y (2011) Monte Carlo simulation and theory of proton NMR transverse relaxation induced by aggregation of magnetic particles used as MRI contrast agents. J Magn Reson 212:139–148PubMedCrossRefGoogle Scholar
  40. 40.
    Yin S, Akita S, Shinozaki M, Li R, Sato T (2008) Synthesis and morphological control of rare earth oxide nanoparticles by solvothermal reaction. J Mater Sci 43:2234–2239CrossRefGoogle Scholar
  41. 41.
    Zhang J, Liu ZG, Lin J, Fang JY (2005) Y2O3 microprisms with trilobal cross section. Cryst Growth Des 5:1527–1530CrossRefGoogle Scholar
  42. 42.
    McIntyre LJ, Prior TJ, Fogg AM (2010) Observation and isolation of layered and framework ytterbium hydroxide phases using in situ energy-dispersive X-ray diffraction. Chem Mater 22:2635–2645CrossRefGoogle Scholar
  43. 43.
    Fang Y-P, Xu A-W, You L-P, Song R-Q, Yu JC, Zhang H-X, Li Q, Liu H-Q (2003) Hydrothermal synthesis of rare earth (Tb, Y) hydroxide and oxide nanotubes. Adv Funct Mater 13:955–960CrossRefGoogle Scholar
  44. 44.
    (1977) Handbook of chemistry and physics. CRC Press, ClevelandGoogle Scholar
  45. 45.
    Gossuin Y, Roch A, Muller RN, Gillis P (2002) An evaluation of the contributions of diffusion and exchange in relaxation enhancement by MRI contrast agents. J Magn Reson 158:36–42PubMedCrossRefGoogle Scholar
  46. 46.
    Mc Connel J (1987) The theory of nuclear magnetic relaxation in liquids. Cambridge university press, CambridgeGoogle Scholar
  47. 47.
    Satoh A, Chantrell RW, Kamiyama S-I, Coverdale GN (1996) Two-dimensional Monte Carlo simulations to capture thick chainlike clusters of ferromagnetic particles in colloidal dispersions. J Colloid Interface Sci 178:620–627CrossRefGoogle Scholar
  48. 48.
    Platas-Iglesias C, Vander Elst L, Zhou W, Muller RN, Geraldes CFG, Mashmeyer T, Peters JA (2002) Zeolite GdNaY nanoparticles with very high relaxitivity for application as contrast agents in magnetic resonance imaging. Chem Eur J 8:5121–5131PubMedCrossRefGoogle Scholar
  49. 49.
    Brodbeck CM, Iton LE (1985) The EPR spectra of Gd3+ and Eu2+ in glassy systems. J Chem Phys 83:4285CrossRefGoogle Scholar
  50. 50.
    Du G, Van Tendeloo G (2005) Preparation and structure analysis of Gd(OH)3 nanorods. Nanotechnology 16:595–597CrossRefGoogle Scholar
  51. 51.
    Reuben J (1975) Electron spin relaxation in aqueous solutions of gadolinium(III)-aquo, cacodylate and bovine serum albumin complexes. J Phys Chem 75:3164CrossRefGoogle Scholar
  52. 52.
    Toth E, Helm L, Kellar KE, Merbach AE (1999) Gd(DTPA-bisamide)alkyl copolymers: a hint for the formation of MRI contrast agents with very high relaxivity. Chem Eur J 5:1202–1211CrossRefGoogle Scholar
  53. 53.
    Zitha-Bovens E, Muller RN, Laurent S, Vander Elst L, Geraldes CFGC, van Bekkum H, Peters JA (2005) Structure and dynamics of lanthanide complexes of TTHA and TTHA-bisamides as studied by NMR, NMRD and EPR. Helv Chim Acta 88:618–632CrossRefGoogle Scholar
  54. 54.
    Brovelli S, Chiodini N, Meinardi F, Lauria A, Lorenzi R, Vodopivec B, Mozzati MC, Paleari A (2009) Confined diffusion of erbium excitations in SnO2 nanoparticles embedded in silica: a time-resolved infrared luminescence study. Phys Rev B 79:153108CrossRefGoogle Scholar
  55. 55.
    Dantelle G, Mortier M, Vivien D (2007) EPR and optical studies of erbium-doped βPbF2 single crystals and nanocrystals in transparent oxyfluoride glass-ceramics. Phys Chem Chem Phys 9:5591–5598PubMedCrossRefGoogle Scholar
  56. 56.
    Abragam A, Bleaney B (1970) Electron paramagnetic resonance. Clarendon press, OxfordGoogle Scholar
  57. 57.
    Bertini I, Capozzi F, Luchinat C, Nicastro G, Xia Z (1993) Water proton relaxation for some lanthanide aqua ions in solution. J Phys Chem 97:6351–6354CrossRefGoogle Scholar
  58. 58.
    Gueron M (1975) Nuclear relaxation in macromolecules by paramagnetic ions: a novel mechanism. J Mag Reson 19:58–66CrossRefGoogle Scholar

Copyright information

© ESMRMB 2012

Authors and Affiliations

  • Quoc Lam Vuong
    • 1
  • Sabine Van Doorslaer
    • 2
  • Jean-Luc Bridot
    • 3
    • 4
  • Corradina Argante
    • 1
  • Gabriela Alejandro
    • 2
    • 5
  • Raphaël Hermann
    • 6
    • 7
  • Sabrina Disch
    • 6
  • Carlos Mattea
    • 8
  • Siegfried Stapf
    • 8
  • Yves Gossuin
    • 1
  1. 1.Biological Physics DepartmentUniversity of Mons—UMONSMonsBelgium
  2. 2.Department of PhysicsUniversity of AntwerpAntwerpBelgium
  3. 3.Department of ChemistryUniversité LavalQuebec CityCanada
  4. 4.Centre de Recherche sur les Matériaux Avancés (CERMA)Université LavalQuebec CityCanada
  5. 5.Centro Atómico Bariloche (CNEA) and CONICETSan Carlos de BarilocheArgentina
  6. 6.Institut für Festkörperforschung, JCNS und JARA-FITForschungszentrum, Jülich GmbHJülichGermany
  7. 7.Faculté des SciencesUniversité de LiègeLiègeBelgium
  8. 8.Fakultät für Mathematik und Naturwissenschaften, FG Technische Physik II/PolymerphysikTechnische Universität IlmenauIlmenauGermany

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