Iron Oxide Nanoparticle-Based MRI Contrast Agents: Characterization and In Vivo Use



Iron oxide nanoparticles are one of the most important materials for magnetic resonance imaging. The possibility of multifunctionalization, lack of toxicity, and variety of compositions make them ideal for many applications. Furthermore, the new generation of nanoparticles for “positive” contrast will increase even more their utility, particularly in the clinic.


Iron Oxide Sentinel Lymph Node Iron Oxide Nanoparticles Transverse Magnetization Core Size 
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.


  1. 1.
    Merbach A, Helm L, Toth E (2013) The chemistry of contrast agents in medical magnetic resonance imaging. Wiley, HobokenCrossRefGoogle Scholar
  2. 2.
    Laurent S, Forge D, Port M, Roch A, Robic C, Vander Elst L et al (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev 108:2064–2110. doi: 10.1021/cr068445e CrossRefGoogle Scholar
  3. 3.
    Tartaj P, Morales MP, Gonzalez-Carreño T, Veintemillas-Verdaguer S, Serna CJ (2011) The iron oxides strike back: from biomedical applications to energy storage devices and photoelectrochemical water splitting. Adv Mater 23:5243–5249CrossRefGoogle Scholar
  4. 4.
    Tartaj P, Morales MP, Veintemillas-verdaguer S, Gonzalez-carreño T, Serna CJ (2006) Synthesis, properties and biomedical applications of magnetic.;16. doi: 10.1016/S1567-2719(05)16005-3
  5. 5.
    Ikeda Y, Nagasaki Y (2011) PEGylation technology in nanomedicine. doi:10.1007/12Google Scholar
  6. 6.
    Moore A, Weissleder R, Bogdanov A Jr (1997) Uptake of dextran-coated monocrystalline iron oxides in tumor cells and macrophages. J Magn Reson Imag JMRI 7:1140–1145CrossRefGoogle Scholar
  7. 7.
    Herranz F, del Morales MP, Roca AG, Desco M, Ruiz-Cabello J (2008) A new method for the rapid synthesis of water stable superparamagnetic nanoparticles. Chem – A Eur J 14:9126–9130. doi: 10.1002/chem.200800755 CrossRefGoogle Scholar
  8. 8.
    Mejías R, Pérez-yagüe S, Gutiérrez L, Cabrera LI, Spada R, Acedo P et al (2011) Biomaterials dimercaptosuccinic acid-coated magnetite nanoparticles for magnetically guided in vivo delivery of interferon gamma for cancer immunotherapy. Biomaterials 32:2938–2952. doi: 10.1016/j.biomaterials.2011.01.008 CrossRefGoogle Scholar
  9. 9.
    Groult H, Ruiz-Cabello J, Lechuga-Vieco AV, Mateo J, Benito M, Bilbao I et al (2014) Phosphatidylcholine-coated iron oxide nanomicelles for in vivo prolonged circulation time with an antibiofouling protein corona. Chem – A Eur J. doi: 10.1002/chem.201404221
  10. 10.
    Estephan ZG, Schlenoff PS, Schlenoff JB (2011) Zwitteration as an alternative to PEGylation. Langmuir 27:6794–6800. doi: 10.1021/la200227b CrossRefGoogle Scholar
  11. 11.
    Bloch F (1946) Nuclear induction. Phys Rev 70:460–474. doi: 10.1103/PhysRev.70.460 CrossRefGoogle Scholar
  12. 12.
    Purcell E, Torrey H, Pound R (1946) Resonance absorption by nuclear magnetic moments in a solid. Phys Rev 69:37–38. doi: 10.1103/PhysRev.69.37 CrossRefGoogle Scholar
  13. 13.
    Torrey H (1956) Bloch equations with diffusion terms. Phys Rev 104:563–565. doi: 10.1103/PhysRev.104.563 CrossRefGoogle Scholar
  14. 14.
    Vuong QL, Berret J-F, Fresnais J, Gossuin Y, Sandre O (2012) A universal scaling law to predict the efficiency of magnetic nanoparticles as MRI T(2)-contrast agents. Adv Healthc Mater 1:502–512. doi: 10.1002/adhm.201200078 CrossRefGoogle Scholar
  15. 15.
    Collins T (2007) ImageJ for microscopy. Biotechniques 43:S25–S30. doi: 10.2144/000112517 CrossRefGoogle Scholar
  16. 16.
    Lim J, Yeap SP, Che HX, Low SC (2013) Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett 8:381. doi: 10.1186/1556-276X-8-381 CrossRefGoogle Scholar
  17. 17.
    Mejías R, Costo R, Roca AG, Arias CF, Veintemillas-Verdaguer S, González-Carreño T et al (2008) Cytokine adsorption/release on uniform magnetic nanoparticles for localized drug delivery. J Control Release Off J Control Release Soc 130:168–174. doi: 10.1016/j.jconrel.2008.05.028 CrossRefGoogle Scholar
  18. 18.
    Selim KMK, Ha Y, Kim S, Chang Y, Kim T, Ho G et al (2007) Surface modification of magnetite nanoparticles using lactobionic acid and their interaction with hepatocytes. 28:710–716. doi: 10.1016/j.biomaterials.2006.09.014
  19. 19.
    Qu H, Caruntu D, Liu H, O’Connor CJ (2011) Water-dispersible iron oxide magnetic nanoparticles with versatile surface functionalities. Langmuir 27:2271–2278. doi: 10.1021/la104471r CrossRefGoogle Scholar
  20. 20.
    Shieh D-B, Cheng F-Y, Su C-H, Yeh C-S, Wu M-T, Wu Y-N et al (2005) Aqueous dispersions of magnetite nanoparticles with NH3+ surfaces for magnetic manipulations of biomolecules and MRI contrast agents. Biomaterials 26:7183–7191. doi: 10.1016/j.biomaterials.2005.05.020 CrossRefGoogle Scholar
  21. 21.
    Kharisov BI, Dias HVR, Kharissova OV, Vázquez A, Peña Y, Gómez I (2014) Solubilization, dispersion and stabilization of magnetic nanoparticles in water and non-aqueous solvents: recent trends. RSC Adv 4:45354–45381. doi: 10.1039/C4RA06902A CrossRefGoogle Scholar
  22. 22.
    Canfarotta F, Piletsky SA (2014) Engineered magnetic nanoparticles for biomedical applications. Adv Healthc Mater 3:160–175. doi: 10.1002/adhm.201300141 CrossRefGoogle Scholar
  23. 23.
    Issa B, Obaidat IM, Albiss BA, Haik Y (2013) Magnetic nanoparticles: surface effects and properties related to biomedicine applications. Int J Mol Sci 14:21266–21305. doi: 10.3390/ijms141121266 CrossRefGoogle Scholar
  24. 24.
    Tuček P, Tučková M, Fišerová E, Tuček J, Kubáček L (2012) Design of experiment for measurement of Langevin function. Meas Sci Rev 12. doi: 10.2478/v10048-012-0019-4
  25. 25.
    Garcia MA, Fernandez Pinel E, de la Venta J, Quesada A, Bouzas V, Fernández JF et al (2009) Sources of experimental errors in the observation of nanoscale magnetism. J Appl Phys 105:013925. doi: 10.1063/1.3060808 CrossRefGoogle Scholar
  26. 26.
    Ortega D, Vélez-Fort E, García DA, García R, Litrán R, Barrera-Solano C et al (2010) Size and surface effects in the magnetic properties of maghemite and magnetite coated nanoparticles. Philos Trans A Math Phys Eng Sci 368:4407–4418. doi: 10.1098/rsta.2010.0172 CrossRefGoogle Scholar
  27. 27.
    Costo R, Bello V, Robic C, Port M, Marco JF, Puerto Morales M et al (2012) Ultrasmall iron oxide nanoparticles for biomedical applications: improving the colloidal and magnetic properties. Langmuir 28:178–185. doi: 10.1021/la203428z CrossRefGoogle Scholar
  28. 28.
    Garcia-Palacios JL (2009) On the statics and dynamics of magneto-anisotropic nanoparticles. Advances in Chemical Physics, vol. 112 (2000) 1–210Google Scholar
  29. 29.
    Egli R (2009) Magnetic susceptibility measurements as a function of temperature and frequency I: inversion theory. Geophys J Int 177:395–420. doi: 10.1111/j.1365-246X.2009.04081.x CrossRefGoogle Scholar
  30. 30.
    Hansen MF, Jönsson PE, Nordblad P, Svedlindh P (2002) Critical dynamics of an interacting magnetic nanoparticle system. J Phys Condens Matter 14:4901–4914. doi: 10.1088/0953-8984/14/19/314 CrossRefGoogle Scholar
  31. 31.
    Raikher YL, Stepanov VI (2008) Magnetic relaxation in a suspension of antiferromagnetic nanoparticles. J Exp Theor Phys 107:435–444. doi: 10.1134/S1063776108090112 CrossRefGoogle Scholar
  32. 32.
    Gutiérrez L, Morales MP, Lázaro FJ (2014) Prospects for magnetic nanoparticles in systemic administration: synthesis and quantitative detection. Phys Chem Chem Phys 16:4456–4464. doi: 10.1039/c3cp54763a CrossRefGoogle Scholar
  33. 33.
    Wang G, Inturi S, Serkova NJ, Merkulov S, McCrae K, Russek SE et al (2014) High-relaxivity superparamagnetic iron oxide nanoworms with decreased immune recognition and long-circulating properties. ACS Nano 8:12437–12449. doi: 10.1021/nn505126b CrossRefGoogle Scholar
  34. 34.
    Casals E, Pfaller T, Duschl A, Oostingh GJ, Puntes V (2010) Time evolution of the nanoparticle protein corona. ACS Nano 4:3623–3632. doi: 10.1021/nn901372t CrossRefGoogle Scholar
  35. 35.
    Barrán-Berdón AL, Pozzi D, Caracciolo G, Capriotti AL, Caruso G, Cavaliere C et al (2013) Time evolution of nanoparticle–protein corona in human plasma: relevance for targeted drug delivery. Langmuir 29:6485–6494. doi: 10.1021/la401192x CrossRefGoogle Scholar
  36. 36.
    Tenzer S, Docter D, Kuharev J, Musyanovych A, Fetz V, Hecht R et al (2013) Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat Nanotechnol 8:772–781. doi: 10.1038/nnano.2013.181 CrossRefGoogle Scholar
  37. 37.
    Herranz F, Morales MP, Roca AG, Vilar R, Ruiz-Cabello J (2008) A new method for the aqueous functionalization of superparamagnetic Fe2O3 nanoparticles. Contrast Media Mol Imaging 3:215–222CrossRefGoogle Scholar
  38. 38.
    Lattuada M, Hatton TA (2007) Functionalization of monodisperse magnetic nanoparticles. Langmuir ACS J Surf Colloids 23:2158–2168. doi: 10.1021/la062092x CrossRefGoogle Scholar
  39. 39.
    Gage SH, Stein BD, Nikoshvili LZ, Matveeva VG, Sulman MG, Sulman EM et al (2013) Functionalization of monodisperse iron oxide NPs and their properties as magnetically recoverable catalysts. Langmuir ACS J Surf Colloids 29:466–473. doi: 10.1021/la304410z CrossRefGoogle Scholar
  40. 40.
    Quarta A, Curcio A, Kakwere H, Pellegrino T (2012) Polymer coated inorganic nanoparticles: tailoring the nanocrystal surface for designing nanoprobes with biological implications. Nanoscale 4. doi: 10.1039/c2nr30271c
  41. 41.
    Maleki H, Simchi A, Imani M, Costa BFO (2012) Size-controlled synthesis of superparamagnetic iron oxide nanoparticles and their surface coating by gold for biomedical applications. J Magn Magn Mater 324:3997–4005. doi: 10.1016/j.jmmm.2012.06.045 CrossRefGoogle Scholar
  42. 42.
    Herranz F, Schmidt-Weber CB, Shamji MH, Narkus A, Ruiz-Cabello J, Vilar R (2012) Superparamagnetic iron oxide nanoparticles conjugated to a grass pollen allergen and an optical probe. Contrast Media Mol Imaging 7:435–439. doi: 10.1002/cmmi.1466 CrossRefGoogle Scholar
  43. 43.
    Rodríguez I, Pérez-Rial S, González-Jimenez J, Pérez-Sánchez J, Herranz F, Beckmann N et al (2008) Magnetic resonance methods and applications in pharmaceutical research. J Pharm Sci 97:3637–3665. doi: 10.1002/jps.21281 CrossRefGoogle Scholar
  44. 44.
    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 113:7033–7039. doi: 10.1021/jp807820s CrossRefGoogle Scholar
  45. 45.
    Mejías R, Pérez-Yagüe S, Roca AG, Pérez N, Villanueva A, Cañete M et al (2010) Liver and brain imaging through dimercaptosuccinic acid-coated iron oxide nanoparticles. Nanomedicine (Lond) 5:397–408. doi: 10.2217/nnm.10.15 CrossRefGoogle Scholar
  46. 46.
    Zhou H-P, Xu C-H, Sun W, Yan C-H (2009) Clean and flexible modification strategy for carboxyl/aldehyde-functionalized upconversion nanoparticles and their optical applications. Adv Funct Mater 19:3892–3900. doi: 10.1002/adfm.200901458 CrossRefGoogle Scholar
  47. 47.
    Xia T, Wang J, Wu C, Meng F, Shi Z, Lian J et al (2012) Novel complex-coprecipitation route to form high quality triethanolamine-coated Fe3O4 nanocrystals: their high saturation magnetizations and excellent water treatment properties. CrystEngComm 14:5741. doi: 10.1039/c2ce25813g CrossRefGoogle Scholar
  48. 48.
    Korpany KV, Habib F, Murugesu M, Blum AS (2013) Stable water-soluble iron oxide nanoparticles using Tiron. Mater Chem Phys 138:29–37. doi: 10.1016/j.matchemphys.2012.10.015 CrossRefGoogle Scholar
  49. 49.
    Liang G, Xiao L, Chen H, Liu Q, Zhang S, Li F et al (2013) Label-free, nucleotide-mediated dispersion of magnetic nanoparticles for “non-sandwich type” MRI-based quantification of enzyme. Biosens Bioelectron 41:78–83. doi: 10.1016/j.bios.2012.07.025 CrossRefGoogle Scholar
  50. 50.
    Hamed A, Fitzgerald AG, Wang LY, Gueorguieva M, Malik R, Melzer A (2013) Characterisation of Mn0 · 7Zn0 · 3Fe2O4 nanoparticles prepared by two stage annealing. Mater Technol 28:339–346. doi: 10.1179/1753555713Y.0000000066 CrossRefGoogle Scholar
  51. 51.
    Towards MRI T2 contrast agents of increased efficiency. (n.d.) J Magn Magn Mater. doi: 10.1010/j.jmmm.2014.10.086
  52. 52.
    Ruiz-Cabello J, Morales MP, Salinas B, Herranz F (2012) Olefin metathesis for the functionalization of superparamagnetic nanoparticles. Bioinspired, Biomim Nanobiomater 1:166–172. doi: 10.1680/bbn.12.00001 CrossRefGoogle Scholar
  53. 53.
    Lin YA, Chalker JM, Davis BG (2009) Olefin metathesis for site-selective protein modification. 959–969. doi: 10.1002/cbic.200900002
  54. 54.
    Li M, Song Y, Cho N, Chang JM, Koo HR, Yi A et al (2011) An HR-MAS MR metabolomics study on breast tissues obtained with core needle biopsy. PLoS One 6, e25563. doi: 10.1371/journal.pone.0025563 CrossRefGoogle Scholar
  55. 55.
    André M, Dumez J-N, Rezig L, Shintu L, Piotto M, Caldarelli S (2014) Complete protocol for slow-spinning high-resolution magic-angle spinning NMR analysis of fragile tissues. Anal Chem 86:10749–10754. doi: 10.1021/ac502792u CrossRefGoogle Scholar
  56. 56.
    Das M, Bandyopadhyay D, Mishra D, Datir S, Dhak P, Jain S et al (2011) “Clickable”, trifunctional magnetite nanoparticles and their chemoselective biofunctionalization. Bioconjug Chem 22:1181–1193. doi: 10.1021/bc2000484 CrossRefGoogle Scholar
  57. 57.
    Polito L, Colombo M, Monti D, Melato S, Caneva E, Prosperi D (2008) Resolving the structure of ligands bound to the surface of superparamagnetic iron oxide nanoparticles by high-resolution magic-angle spinning NMR spectroscopy. J Am Chem Soc 130:12712–12724. doi: 10.1021/ja802479n CrossRefGoogle Scholar
  58. 58.
    Groult H, Ruiz-Cabello J, Pellico J, Lechuga-Vieco AV, Bhavesh R, Zamai M et al (2014) Parallel multifunctionalization of nanoparticles: a one-step modular approach for in vivo imaging. Bioconjug Chem(in press). doi: 10.1021/bc500536y
  59. 59.
    Chen H, Liu S, Li Y, Deng C, Zhang X, Yang P (2011) Development of oleic acid-functionalized magnetite nanoparticles as hydrophobic probes for concentrating peptides with MALDI-TOF-MS analysis. Proteomics 11:890–897. doi: 10.1002/pmic.201000509 CrossRefGoogle Scholar
  60. 60.
    Kim BH, Shin K, Kwon SG, Jang Y, Lee H-S, Lee H et al (2013) Sizing by weighing: characterizing sizes of ultrasmall-sized iron oxide nanocrystals using MALDI-TOF mass spectrometry. J Am Chem Soc 135:2407–2410. doi: 10.1021/ja310030c CrossRefGoogle Scholar
  61. 61.
    Chung J, Yu J-S, Kim DJ, Chung J-J, Kim JH, Kim KW (2011) Hypervascular hepatocellular carcinoma in the cirrhotic liver: diffusion-weighted imaging versus superparamagnetic iron oxide-enhanced MRI. Magn Reson Imaging 29:1235–1243. doi: 10.1016/j.mri.2011.07.025 CrossRefGoogle Scholar
  62. 62.
    Zhao S, Wang Y, Gao C, Zhang J, Bao H, Wang Z et al (2014) Superparamagnetic iron oxide magnetic nanomaterial-labeled bone marrow mesenchymal stem cells for rat liver repair after hepatectomy. J Surg Res 191:290–301. doi: 10.1016/j.jss.2014.03.064 CrossRefGoogle Scholar
  63. 63.
    Teerasamit W, Saiviroonporn P, Pongpaibul A, Korpraphong P (2014) Benefit of double contrast MRI in diagnosis of hepatocellular carcinoma in patients with chronic liver diseases. J Med Assoc Thai 97:540–547Google Scholar
  64. 64.
    Zhao J, Vykoukal J, Abdelsalam M, Recio-Boiles A, Huang Q, Qiao Y et al (2014) Stem cell-mediated delivery of SPIO-loaded gold nanoparticles for the theranosis of liver injury and hepatocellular carcinoma. Nanotechnology 25:405101. doi: 10.1088/0957-4484/25/40/405101 CrossRefGoogle Scholar
  65. 65.
    Groult H, Ruiz-Cabello J, Lechuga-Vieco AV, Mateo J, Benito M, Bilbao I, Martínez-Alcázar MP, Lopez JA, Vázquez J, Herranz FF (2014) Phosphatidylcholine-Coated Iron Oxide Nanomicelles for In Vivo Prolonged Circulation Time with an Antibiofouling Protein Corona. Chem - A Eur J 20:16662–16671CrossRefGoogle Scholar
  66. 66.
    Qi H, Li Z, Du K, Mu K, Zhou Q, Liang S et al (2014) Transferrin-targeted magnetic/fluorescence micelles as a specific bi-functional nanoprobe for imaging liver tumor. Nanoscale Res Lett 9:595. doi: 10.1186/1556-276X-9-595 CrossRefGoogle Scholar
  67. 67.
    Yang R-M, Fu C-P, Li N-N, Wang L, Xu X-D, Yang D-Y et al (2014) Glycosaminoglycan-targeted iron oxide nanoparticles for magnetic resonance imaging of liver carcinoma. Mater Sci Eng C Mater Biol Appl 45:556–563. doi: 10.1016/j.msec.2014.09.038 CrossRefGoogle Scholar
  68. 68.
    Yu MK, Kim D, Lee I-H, So J-S, Jeong YY, Jon S (2011) Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small 7:2241–2249. doi: 10.1002/smll.201100472 CrossRefGoogle Scholar
  69. 69.
    Li Q, Qi H, Zhou H-X, Deng C-Y, Zhu H, Li J-F et al (2011) Detection of micrometastases in peripheral blood of non-small cell lung cancer with a refined immunomagnetic nanoparticle enrichment assay. Int J Nanomedicine 6:2175–2181. doi: 10.2147/IJN.S24731 CrossRefGoogle Scholar
  70. 70.
    Corem-Salkmon E, Perlstein B, Margel S (2012) Design of near-infrared fluorescent bioactive conjugated functional iron oxide nanoparticles for optical detection of colon cancer. Int J Nanomedicine 7:5517–5527. doi: 10.2147/IJN.S33710 Google Scholar
  71. 71.
    Shao H, Chung J, Balaj L, Charest A, Bigner DD, Carter BS et al (2012) Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 18:1835–1840. doi: 10.1038/nm.2994 CrossRefGoogle Scholar
  72. 72.
    Niu C, Wang Z, Lu G, Krupka TM, Sun Y, You Y et al (2013) Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes. Biomaterials 34:2307–2317. doi: 10.1016/j.biomaterials.2012.12.003 CrossRefGoogle Scholar
  73. 73.
    Shahbazi-Gahrouei D, Abdolahi M (2013) Superparamagnetic iron oxide-C595: potential MR imaging contrast agents for ovarian cancer detection. J Med Phys 38:198–204. doi: 10.4103/0971-6203.121198 CrossRefGoogle Scholar
  74. 74.
    Lee JY, Kim J-H, Bae KH, Oh MH, Kim Y, Kim JS et al (2014) Low-density lipoprotein-mimicking nanoparticles for tumor-targeted theranostic applications. Small. doi: 10.1002/smll.201303277 Google Scholar
  75. 75.
    Tse BW-C, Cowin GJ, Soekmadji C, Jovanovic L, Vasireddy RS, Ling M-T et al (2014) PSMA-targeting iron oxide magnetic nanoparticles enhance MRI of preclinical prostate cancer. Nanomedicine (Lond):1–12. doi: 10.2217/nnm.14.122
  76. 76.
    Groult H, Ruiz-Cabello J, Pellico J, Lechuga-Vieco AV, Bhavesh R, Zamai M et al (2014) Parallel multifunctionalization of nanoparticles: a one-step modular approach for in vivo imaging. Bioconjug Chem. doi: 10.1021/bc500536y Google Scholar
  77. 77.
    Wang L, Zhong X, Qian W, Huang J, Cao Z, Yu Q, Lipowska, M, Lin R, Wang A, Yang L, Mao H (2014) Ultrashort Echo Time (UTE) imaging of receptor targeted magnetic iron oxide nanoparticles in mouse tumor models. J Magn Reson Imaging 40:1071–1081CrossRefGoogle Scholar
  78. 78.
    Briley-Saebo KC, Cho YS, Shaw PX, Ryu SK, Mani V, Dickson S et al (2011) Targeted iron oxide particles for in vivo magnetic resonance detection of atherosclerotic lesions with antibodies directed to oxidation-specific epitopes. J Am Coll Cardiol 57:337–347. doi: 10.1016/j.jacc.2010.09.023 CrossRefGoogle Scholar
  79. 79.
    Wagner S, Schnorr J, Ludwig A, Stangl V, Ebert M, Hamm B et al (2013) Contrast-enhanced MR imaging of atherosclerosis using citrate-coated superparamagnetic iron oxide nanoparticles: calcifying microvesicles as imaging target for plaque characterization. Int J Nanomedicine 8:767–779. doi: 10.2147/IJN.S38702 Google Scholar
  80. 80.
    Wen S, Liu D-F, Cui Y, Harris SS, Chen Y, Li KC et al (2013) In vivo MRI detection of carotid atherosclerotic lesions and kidney inflammation in ApoE-deficient mice by using LOX-1 targeted iron nanoparticles. Nanomed Nanotechnol, Biol Med. doi: 10.1016/j.nano.2013.09.009
  81. 81.
    You DG, Saravanakumar G, Son S, Han HS, Heo R, Kim K et al (2014) Dextran sulfate-coated superparamagnetic iron oxide nanoparticles as a contrast agent for atherosclerosis imaging. Carbohydr Polym 101:1225–1233. doi: 10.1016/j.carbpol.2013.10.068 CrossRefGoogle Scholar
  82. 82.
    Pellico J, Lechuga-Vieco AV, Benito M, García-Segura JM, Fuster V, Ruiz-Cabello J et al (2014) Microwave-driven synthesis of bisphosphonate nanoparticles allows in vivo visualisation of atherosclerotic plaque. RSC Adv 5:1661–1665. doi: 10.1039/C4RA13824D CrossRefGoogle Scholar
  83. 83.
    Le Bihan D, Joly O, Aso T, Uhrig L, Poupon C, Tani N et al (2012) Brain tissue water comes in two pools: evidence from diffusion and R2’ measurements with USPIOs in non human primates. Neuroimage 62:9–16. doi: 10.1016/j.neuroimage.2012.05.011 CrossRefGoogle Scholar
  84. 84.
    Thomsen LB, Linemann T, Pondman KM, Lichota J, Kim KS, Pieters RJ et al (2013) Uptake and transport of superparamagnetic iron oxide nanoparticles through human brain capillary endothelial cells. ACS Chem Neurosci 4:1352–1360. doi: 10.1021/cn400093z CrossRefGoogle Scholar
  85. 85.
    Mori Y, Chen T, Fujisawa T, Kobashi S, Ohno K, Yoshida S, Tago Y, Komai Y, Hata Y, Yoshioka Y (2014) From Cartoon to Real Time MRI: In Vivo Monitoring of Phagocyte Migration in Mouse Brain. Sci Rep 4:6997CrossRefGoogle Scholar
  86. 86.
    Gauberti M, Montagne A, Quenault A, Vivien D (2014) Molecular magnetic resonance imaging of brain-immune interactions. Front Cell Neurosci 8:389. doi: 10.3389/fncel.2014.00389 CrossRefGoogle Scholar
  87. 87.
    Sart S, Bejarano FC, Baird MA, Yan Y, Rosenberg JT, Ma T et al (2015) Intracellular labeling of mouse embryonic stem cell-derived neural progenitor aggregates with micron-sized particles of iron oxide. Cytotherapy 17:98–111. doi: 10.1016/j.jcyt.2014.09.008 CrossRefGoogle Scholar
  88. 88.
    Choi SH, Moon WK (2010) Contrast-enhanced MR imaging of lymph nodes in cancer patients. Korean J Radiol 11:383–394. doi: 10.3348/kjr.2010.11.4.383 CrossRefGoogle Scholar
  89. 89.
    Weissleder R, Elizondo G, Wittenberg J, Lee AS, Josephson L, Brady TJ (1990) Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiology 175:494–498. doi: 10.1148/radiology.175.2.2326475 CrossRefGoogle Scholar
  90. 90.
    Moghimi S, Bonnemain B (1999) Subcutaneous and intravenous delivery of diagnostic agents to the lymphatic system: applications in lymphoscintigraphy and indirect lymphography. Adv Drug Deliv Rev 37:295–312CrossRefGoogle Scholar
  91. 91.
    Stets C, Brandt S, Wallis F, Buchmann J, Gilbert FJ, Heywang-Köbrunner SH (2002) Axillary lymph node metastases: a statistical analysis of various parameters in MRI with USPIO. J Magn Reson Imaging 16:60–68. doi: 10.1002/jmri.10134 CrossRefGoogle Scholar
  92. 92.
    Pultrum BB, van der Jagt EJ, van Westreenen HL, van Dullemen HM, Kappert P, Groen H et al (2009) Detection of lymph node metastases with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging in oesophageal cancer: a feasibility study. Cancer Imaging 9:19–28. doi: 10.1102/1470-7330.2009.0004 CrossRefGoogle Scholar
  93. 93.
    Anzai Y, Prince MR (n.d.) Iron oxide-enhanced MR lymphography: the evaluation of cervical lymph node metastases in head and neck cancer. J Magn Reson Imaging 7:75–81Google Scholar
  94. 94.
    Tokuhara T, Tanigawa N, Matsuki M, Nomura E, Mabuchi H, Lee S-W et al (2008) Evaluation of lymph node metastases in gastric cancer using magnetic resonance imaging with ultrasmall superparamagnetic iron oxide (USPIO): diagnostic performance in post-contrast images using new diagnostic criteria. Gastric Cancer 11:194–200. doi: 10.1007/s10120-008-0480-9 CrossRefGoogle Scholar
  95. 95.
    Yoo R-E, Choi SH, Cho HR, Jeon B-S, Kwon E, Kim E-G et al (2014) Magnetic resonance imaging diagnosis of metastatic lymph nodes in a rabbit model: efficacy of PJY10, a new ultrasmall superparamagnetic iron oxide agent, with monodisperse iron oxide core and multiple-interaction ligands. PLoS One 9, e107583. doi: 10.1371/journal.pone.0107583 CrossRefGoogle Scholar
  96. 96.
    Mack MG, Balzer JO, Straub R, Eichler K, Vogl TJ (2002) Superparamagnetic iron oxide-enhanced MR imaging of head and neck lymph nodes. Radiology 222:239–244. doi: 10.1148/radiol.2221010225 CrossRefGoogle Scholar
  97. 97.
    McCauley TR, Rifkin MD, Ledet CA (2002) Pelvic lymph node visualization with MR imaging using local administration of ultra-small superparamagnetic iron oxide contrast. J Magn Reson Imaging 15:492–497CrossRefGoogle Scholar
  98. 98.
    Hudgins PA, Anzai Y, Morris MR, Lucas MA (2002) Ferumoxtran-10, a superparamagnetic iron oxide as a magnetic resonance enhancement agent for imaging lymph nodes: a phase 2 dose study. AJNR Am J Neuroradiol 23:649–656Google Scholar
  99. 99.
    Sigal R, Vogl T, Casselman J, Moulin G, Veillon F, Hermans R et al (2002) Lymph node metastases from head and neck squamous cell carcinoma: MR imaging with ultrasmall superparamagnetic iron oxide particles (Sinerem MR) – results of a phase-III multicenter clinical trial. Eur Radiol 12:1104–1113. doi: 10.1007/s003300101130 CrossRefGoogle Scholar
  100. 100.
    Rockall AG, Sohaib SA, Harisinghani MG, Babar SA, Singh N, Jeyarajah AR et al (2005) Diagnostic performance of nanoparticle-enhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol 23:2813–2821. doi: 10.1200/JCO.2005.07.166 CrossRefGoogle Scholar
  101. 101.
    Harisinghani MG, Saksena MA, Hahn PF, King B, Kim J, Torabi MT et al (2006) Ferumoxtran-10-enhanced MR lymphangiography: does contrast-enhanced imaging alone suffice for accurate lymph node characterization? AJR Am J Roentgenol 186:144–148. doi: 10.2214/AJR.04.1287 CrossRefGoogle Scholar
  102. 102.
    Stadnik TW, Everaert H, Makkat S, Sacré R, Lamote J, Bourgain C (2006) Breast imaging. Preoperative breast cancer staging: comparison of USPIO-enhanced MR imaging and 18F-fluorodeoxyglucose (FDC) positron emission tomography (PET) imaging for axillary lymph node staging–initial findings. Eur Radiol 16:2153–2160. doi: 10.1007/s00330-006-0276-4 CrossRefGoogle Scholar
  103. 103.
    Harisinghani M, Ross RW, Guimaraes AR, Weissleder R (2007) Utility of a new bolus-injectable nanoparticle for clinical cancer staging. Neoplasia 9:1160–1165CrossRefGoogle Scholar
  104. 104.
    Guimaraes AR, Tabatabei S, Dahl D, McDougal WS, Weissleder R, Harisinghani MG (2008) Pilot study evaluating use of lymphotrophic nanoparticle-enhanced magnetic resonance imaging for assessing lymph nodes in renal cell cancer. Urology 71:708–712. doi: 10.1016/j.urology.2007.11.096 CrossRefGoogle Scholar
  105. 105.
    Heesakkers RAM, Hövels AM, Jager GJ, van den Bosch HCM, Witjes JA, Raat HPJ et al (2008) MRI with a lymph-node-specific contrast agent as an alternative to CT scan and lymph-node dissection in patients with prostate cancer: a prospective multicohort study. Lancet Oncol 9:850–856. doi: 10.1016/S1470-2045(08)70203-1 CrossRefGoogle Scholar
  106. 106.
    Ross RW, Zietman AL, Xie W, Coen JJ, Dahl DM, Shipley WU et al (n.d.) Lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) identifies occult lymph node metastases in prostate cancer patients prior to salvage radiation therapy. Clin Imaging 33:301–5. doi: 10.1016/j.clinimag.2009.01.013
  107. 107.
    Kimura K, Tanigawa N, Matsuki M, Nohara T, Iwamoto M, Sumiyoshi K et al (2010) High-resolution MR lymphography using ultrasmall superparamagnetic iron oxide (USPIO) in the evaluation of axillary lymph nodes in patients with early stage breast cancer: preliminary results. Breast Cancer 17:241–246. doi: 10.1007/s12282-009-0143-7 CrossRefGoogle Scholar
  108. 108.
    Johnson L, Pinder SE, Douek M (2013) Deposition of superparamagnetic iron-oxide nanoparticles in axillary sentinel lymph nodes following subcutaneous injection. Histopathology 62:481–486. doi: 10.1111/his.12019 CrossRefGoogle Scholar
  109. 109.
    Thill M, Kurylcio A, Welter R, van Haasteren V, Grosse B, Berclaz G et al (2014) The Central-European SentiMag study: sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. radioisotope. Breast 23:175–179. doi: 10.1016/j.breast.2014.01.004 CrossRefGoogle Scholar
  110. 110.
    Birkhäuser FD, Studer UE, Froehlich JM, Triantafyllou M, Bains LJ, Petralia G et al (2013) Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer. Eur Urol 64:953–960. doi: 10.1016/j.eururo.2013.07.032 CrossRefGoogle Scholar
  111. 111.
    Michel SCA, Keller TM, Fröhlich JM, Fink D, Caduff R, Seifert B et al (2002) Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall superparamagnetic iron oxide enhancement. Radiology 225:527–536. doi: 10.1148/radiol.2252011605 CrossRefGoogle Scholar
  112. 112.
    Anzai Y, Piccoli CW, Outwater EK, Stanford W, Bluemke DA, Nurenberg P et al (2003) Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology 228:777–788. doi: 10.1148/radiol.2283020872 CrossRefGoogle Scholar
  113. 113.
    Heesakkers RAM, Fütterer JJ, Hövels AM, van den Bosch HCM, Scheenen TWJ, Hoogeveen YL et al (2006) Prostate cancer evaluated with ferumoxtran-10-enhanced T2*-weighted MR Imaging at 1.5 and 3.0 T: early experience. Radiology 239:481–487. doi: 10.1148/radiol.2392050411 CrossRefGoogle Scholar
  114. 114.
    Saksena M, Harisinghani M, Hahn P, Kim J, Saokar A, King B et al (2006) Comparison of lymphotropic nanoparticle-enhanced MRI sequences in patients with various primary cancers. AJR Am J Roentgenol 187:W582–W588. doi: 10.2214/AJR.05.0873 CrossRefGoogle Scholar
  115. 115.
    Engelen SME, Beets-Tan RGH, Lahaye MJ, Lammering G, Jansen RLH, van Dam RM et al (2010) MRI after chemoradiotherapy of rectal cancer: a useful tool to select patients for local excision. Dis Colon Rectum 53:979–986. doi: 10.1007/DCR.0b013e3181dc64dc CrossRefGoogle Scholar
  116. 116.
    Rubio IT, Diaz-Botero S, Esgueva A, Rodriguez R, Cortadellas T, Cordoba O et al (2014) The superparamagnetic iron oxide is equivalent to the Tc99 radiotracer method for identifying the sentinel lymph node in breast cancer. Eur J Surg Oncol. doi: 10.1016/j.ejso.2014.11.006 Google Scholar
  117. 117.
    Briley-Saebo KC, Mulder WJM, Mani V, Hyafil F, Amirbekian V, Aguinaldo JGS et al (2007) Magnetic resonance imaging of vulnerable atherosclerotic plaques: current imaging strategies and molecular imaging probes. J Magn Reson Imaging 26:460–479. doi: 10.1002/jmri.20989 CrossRefGoogle Scholar
  118. 118.
    McAteer MA, Akhtar AM, von Zur Muhlen C, Choudhury RP (2010) An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis 209:18–27. doi: 10.1016/j.atherosclerosis.2009.10.009 CrossRefGoogle Scholar
  119. 119.
    Ross R (1999) Atherosclerosis–an inflammatory disease. N Engl J Med 340:115–126. doi: 10.1056/NEJM199901143400207 CrossRefGoogle Scholar
  120. 120.
    Sanz J, Fayad ZA (2008) Imaging of atherosclerotic cardiovascular disease. Nature 451:953–957. doi: 10.1038/nature06803 CrossRefGoogle Scholar
  121. 121.
    Wildgruber M (2013) Molecular imaging of inflammation in atherosclerosis. Theranostics 3:865–884. doi: 10.7150/thno.5771 CrossRefGoogle Scholar
  122. 122.
    Corti R, Fuster V (2011) Imaging of atherosclerosis: magnetic resonance imaging. Eur Heart J 32:1709–1719b. doi: 10.1093/eurheartj/ehr068 CrossRefGoogle Scholar
  123. 123.
    Sanz J, Moreno PR, Fuster V (2012) The year in atherothrombosis. J Am Coll Cardiol 60:932–942. doi: 10.1016/j.jacc.2012.04.045 CrossRefGoogle Scholar
  124. 124.
    Otsuka F, Fuster V, Narula J, Virmani R (2012) Omnipresent atherosclerotic disease: time to depart from analysis of individual vascular beds. Mt Sinai J Med 79:641–653. doi: 10.1002/msj.21353 CrossRefGoogle Scholar
  125. 125.
    Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS et al (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329. doi: 10.1038/nature11260 CrossRefGoogle Scholar
  126. 126.
    Hermann S, Starsichova A, Waschkau B, Kuhlmann M, Wenning C, Schober O et al (2012) Non-FDG imaging of atherosclerosis: Will imaging of MMPs assess plaque vulnerability? J Nucl Cardiol 19:609–617. doi: 10.1007/s12350-012-9553-6 CrossRefGoogle Scholar
  127. 127.
    Schmitz SA, Coupland SE, Gust R, Winterhalter S, Wagner S, Kresse M et al (2000) Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits. Invest Radiol 35:460–471CrossRefGoogle Scholar
  128. 128.
    Schmitz SA, Taupitz M, Wagner S, Wolf KJ, Beyersdorff D, Hamm B (2001) Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles. J Magn Reson Imaging JMRI 14:355–361CrossRefGoogle Scholar
  129. 129.
    Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF (2001) Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 103:415–422CrossRefGoogle Scholar
  130. 130.
    Schmitz SA, Taupitz M, Wagner S, Coupland SE, Gust R, Nikolova A et al (2002) Iron-oxide-enhanced magnetic resonance imaging of atherosclerotic plaques: postmortem analysis of accuracy, inter-observer agreement, and pitfalls. Invest Radiol 37:405–411CrossRefGoogle Scholar
  131. 131.
    Kooi ME, Cappendijk VC, Cleutjens KBJM, Kessels AGH, Kitslaar PJEHM, Borgers M et al (2003) Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 107:2453–2458. doi: 10.1161/01.CIR.0000068315.98705.CC CrossRefGoogle Scholar
  132. 132.
    Schmitz SA, Winterhalter S, Schiffler S, Gust R, Wagner S, Kresse M et al (2001) USPIO-enhanced direct MR imaging of thrombus: preclinical evaluation in rabbits. Radiology 221:237–243. doi: 10.1148/radiol.2211001632 CrossRefGoogle Scholar
  133. 133.
    Sadeghi MM, Glover DK, Lanza GM, Fayad ZA, Johnson LL (2010) Imaging atherosclerosis and vulnerable plaque. J Nucl Med 51:51S–65S. doi: 10.2967/jnumed.109.068163 CrossRefGoogle Scholar
  134. 134.
    Sosnovik DE, Nahrendorf M, Weissleder R (2008) Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol 103:122–130. doi: 10.1007/s00395-008-0710-7 CrossRefGoogle Scholar
  135. 135.
    Tang TY, Muller KH, Graves MJ, Li ZY, Walsh SR, Young V et al (2009) Iron oxide particles for atheroma imaging. Arterioscler Thromb Vasc Biol 29:1001–1008. doi: 10.1161/ATVBAHA.108.165514 CrossRefGoogle Scholar
  136. 136.
    Satomi T, Ogawa M, Mori I, Ishino S, Kubo K, Magata Y et al (2013) Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall superparamagnetic iron oxide. J Nucl Med 54:999–1004. doi: 10.2967/jnumed.112.110551 CrossRefGoogle Scholar
  137. 137.
    Segers FME, den Adel B, Bot I, van der Graaf LM, van der Veer EP, Gonzalez W et al (2013) Scavenger receptor-AI-targeted iron oxide nanoparticles for in vivo MRI detection of atherosclerotic lesions. Arterioscler Thromb Vasc Biol 33:1812–1819. doi: 10.1161/ATVBAHA.112.300707 CrossRefGoogle Scholar
  138. 138.
    Kelly KA (2005) Detection of vascular adhesion molecule-1 expression using a novel multimodal nanoparticle. Circ Res 96:327–336. doi: 10.1161/01.RES.0000155722.17881.dd CrossRefGoogle Scholar
  139. 139.
    Nahrendorf M, Jaffer FA, Kelly KA, Sosnovik DE, Aikawa E, Libby P et al (2006) Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 114:1504–1511. doi: 10.1161/CIRCULATIONAHA.106.646380 CrossRefGoogle Scholar
  140. 140.
    Woollard KJ, Chin-Dusting J (2007) Therapeutic targeting of p-selectin in atherosclerosis. Inflamm Allergy Drug Targets 6:69–74CrossRefGoogle Scholar
  141. 141.
    Jacobin-Valat M-J, Deramchia K, Mornet S, Hagemeyer CE, Bonetto S, Robert R et al (2011) MRI of inducible P-selectin expression in human activated platelets involved in the early stages of atherosclerosis. NMR Biomed 24:413–424. doi: 10.1002/nbm.1606 Google Scholar
  142. 142.
    Smith BR, Heverhagen J, Knopp M, Schmalbrock P, Shapiro J, Shiomi M et al (2007) Localization to atherosclerotic plaque and biodistribution of biochemically derivatized superparamagnetic iron oxide nanoparticles (SPIONs) contrast particles for magnetic resonance imaging (MRI). Biomed Microdevices 9:719–727. doi: 10.1007/s10544-007-9081-3 CrossRefGoogle Scholar
  143. 143.
    Pellico J, Lechuga-Vieco AV, Benito M, García-Segura JM, Fuster V, Ruiz-Cabello J et al (2015) Microwave-driven synthesis of bisphosphonate nanoparticles allows in vivo visualisation of atherosclerotic plaque. RSC Adv 5:1661–1665. doi: 10.1039/C4RA13824D CrossRefGoogle Scholar
  144. 144.
    Ahlström KH, Johansson LO, Rodenburg JB, Ragnarsson AS, Akeson P, Börseth A (1999) Pulmonary MR angiography with ultrasmall superparamagnetic iron oxide particles as a blood pool agent and a navigator echo for respiratory gating: pilot study. Radiology 211:865–869. doi: 10.1148/radiology.211.3.r99jn10865 CrossRefGoogle Scholar
  145. 145.
    Sigovan M, Boussel L, Sulaiman A, Sappey-Marinier D, Alsaid H, Desbleds-Mansard C et al (2009) Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial experience in animal model. Radiology 252:401–409. doi: 10.1148/radiol.2522081484 CrossRefGoogle Scholar
  146. 146.
    Schnorr J, Taupitz M, Schellenberger EA, Warmuth C, Fahlenkamp UL, Wagner S et al (2012) Cardiac magnetic resonance angiography using blood-pool contrast agents: comparison of citrate-coated very small superparamagnetic iron oxide particles with gadofosveset trisodium in pigs. Rofo 184:105–112. doi: 10.1055/s-0031-1281982 CrossRefGoogle Scholar
  147. 147.
    Wagner M, Wagner S, Schnorr J, Schellenberger E, Kivelitz D, Krug L et al (2011) Coronary MR angiography using citrate-coated very small superparamagnetic iron oxide particles as blood-pool contrast agent: initial experience in humans. J Magn Reson Imaging 34:816–823. doi: 10.1002/jmri.22683 CrossRefGoogle Scholar
  148. 148.
    Tanimoto A, Yuasa Y, Hiramatsu K (n.d.) Enhancement of phase-contrast MR angiography with superparamagnetic iron oxide. J Magn Reson Imaging;8:446–450Google Scholar
  149. 149.
    Schmitz SA, Albrecht T, Wolf KJ (1999) MR angiography with superparamagnetic iron oxide: feasibility study. Radiology 213:603–607. doi: 10.1148/radiology.213.2.r99oc24603 CrossRefGoogle Scholar
  150. 150.
    Kim BH, Lee N, Kim H, An K, Park YI, Choi Y et al (2011) Large-scale synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T 1 magnetic resonance imaging contrast agents. J Am Chem Soc 133:12624–12631. doi: 10.1021/ja203340u CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Advanced Imaging UnitCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBERESMadridSpain
  2. 2.Instituto de Ciencia de Materiales de Madrid (ICMM)/CSICCantoblancoSpain
  3. 3.Department of Physical Chemistry, Faculty of PharmacyComplutense UniversityMadridSpain

Personalised recommendations