Determining the Relaxivity Values of Protein Cage-Templated Nanoparticles Using Magnetic Resonance Imaging

  • Barindra Sana
  • Sierin LimEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1252)


The application of magnetic resonance imaging (MRI) is often limited by low magnetic relaxivity of currently used contrast agents. This problem can be addressed by developing more sensitive contrast agents by synthesizing new types of metal complex or metallic nanoparticles. Protein cage has been used as a template in biological synthesis of magnetic nanoparticles. The magnetic nanoparticle-protein cage composites have been reported to have high magnetic relaxivity, which implies their potential application as an MRI contrast agent. The magnetic relaxivity is determined by measuring longitudinal and transverse magnetic relaxivities of the potential agent. The commonly performed techniques are field-cycling NMR relaxometry (also known as variable field relaxometry or nuclear magnetic relaxation dispersion (NMRD) profiling) and in vitro or in vivo MRI relaxometry. Here, we describe techniques for the synthesis of nanoparticle-protein cage composite and determination of their magnetic relaxivities by in vitro MR image acquisition and data processing. In this method, longitudinal and transverse relaxivities are calculated by measuring relaxation rates of water hydrogen nuclei at different nanoparticle-protein cage composite concentrations.

Key words

Magnetic relaxivity Ferritin Nanoparticle MRI Imaging Protein cage 



The authors thank Dr. Cher Heng Tan at Tan Tock Seng Hospital, Singapore, for technical advices on magnetic resonance imaging. The work is supported by Singapore National Medical Research Council New Investigator Grant (NMRC/NIG/1073/2012)


  1. 1.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RL (1999) Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99:2293–2352PubMedCrossRefGoogle Scholar
  2. 2.
    Bulte JW, Kraitchman DL (2004) Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed 17:484–499PubMedCrossRefGoogle Scholar
  3. 3.
    Lu J, Ma S, Sun J, Xia C, Liu C, Wang Z, Zhao X, Gao F, Gong Q, Song B, Shuai X, Ai H, Gu Z (2009) Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging. Biomaterials 30:2919–2928PubMedCrossRefGoogle Scholar
  4. 4.
    Weissleder R, Mahmood U (2001) Molecular imaging. Radiology 219:316–333PubMedCrossRefGoogle Scholar
  5. 5.
    Kubicek V, Toth E (2009) Design and function of metal complexes as contrast agents in MRI. Adv Inorg Chem 61:63–129CrossRefGoogle Scholar
  6. 6.
    Reimer P, Balzer T (2003) Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol 3:1266–1276Google Scholar
  7. 7.
    Bleicher AG, Kanal E (2008) Assessment of adverse reaction rates to a newly approved MRI contrast agent: review of 23,553 administrations of gadobenate dimeglumine. Am J Roentgenol 191:W307–W311CrossRefGoogle Scholar
  8. 8.
    Wang YXJ (2011) Super paramagnetic iron oxide based MRI contrast agents: current status of clinical applications. Quant Imaging Med Surg 1:35–40PubMedPubMedCentralGoogle Scholar
  9. 9.
    Yalappu MM, Othman SF, Curtis ET, Gupta BK, Jaggi M, Chauhan SC (2010) Multi-functional magnetic nanoparticles for magnetic resonance imaging and cancer therapy. Biomaterials 32:1890–1905CrossRefGoogle Scholar
  10. 10.
    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 2:86–102PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Koylu MZ, Asubay S, Yilmaz A (2009) Determination of proton relaxivities of Mn(II), Cu(II) and Cr(III) added to solutions of serum proteins. Molecules 14:1537–1545PubMedCrossRefGoogle Scholar
  12. 12.
    Yang JJ, Yang J, Wei L, Zurkiya O, Yang W, Li S, Zou J, Maniccia AL, Mao H, Zhao F, Malchow R, Zhao S, Johnson J, Hu X, Krogstad E, Liu ZR (2008) Rational design of protein-based MRI contrast agents. J Am Chem Soc 130:9260–9267PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Galvez N, Fernandez B, Valero E, Sanchez P, Cuesta R, Dominguez-Vera JM (2008) Apoferritin as a nanoreactor for preparing metallic nanoparticles. Comp Rendus Chim 11:1207–1212CrossRefGoogle Scholar
  14. 14.
    Yoshizawa K, Iwahori K, Sugimoto K, Yamashita I (2006) Fabrication of gold sulfide nanoparticles using the protein cage of apoferritin. Chem Lett 35:1192–1193CrossRefGoogle Scholar
  15. 15.
    Aime S, Frullano L, Crich SG (2002) Compartmentalization of a gadolinium complex in the apoferritin cavity: a route to obtain high relaxivity contrast agents for magnetic resonance imaging. Angew Chem Int Ed 41:1017–1019CrossRefGoogle Scholar
  16. 16.
    Crich SG, Bussolati B, Tei L, Grange C, Esposito G, Lanzardo S, Camussi G, Aime S (2006) Magnetic resonance visualization of tumor angiogenesis by targeting neural cell adhesion molecules with the highly sensitive gadolinium-loaded apoferritin probe. Cancer Res 66:9196–9201CrossRefGoogle Scholar
  17. 17.
    Sanchez P, Valero E, Galvez N, Dominguez-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
  18. 18.
    Uchida M, Terashima M, Cunningham CH, Suzuki Y, Willitis DA, Yang PC, Tsao PS, McConnell MV, Young MJ, Douglas T (2008) A human ferritin iron oxide nano-composite magnetic resonance contrast agent. Magn Reson Med 60:1073–1081PubMedCrossRefGoogle Scholar
  19. 19.
    Sana B, Johnson E, Sheah K, Poh CL, Lim S (2010) Iron based ferritin nanocore as a contrast agent. Biointerphases 5:AF48–AF52CrossRefGoogle Scholar
  20. 20.
    Sana B, Poh CL, Lim S (2012) A manganese-ferritin nanocomposites as an ultrasensitive T2 contrast agent. Chem Commun 48:862–864CrossRefGoogle Scholar
  21. 21.
    Sana B, Calista M, Lim S (2012) Protein cage assisted metal-protein nanocomposite synthesis: optimization of loading conditions. AIP Conf Proc 1502:82–96CrossRefGoogle Scholar
  22. 22.
    Qiu H, Dong X, Sana B, Peng T, Parapelle D, Chen P, Lim S (2013) Ferritin-templated synthesis and self-assembly of Pt nanoparticles on monolithic porous graphene network for electrocatalysis in fuel cell. ACS Appl Mater Interfaces 5:782–787PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.School of Chemical and Biomedical EngineeringNanyang Technological UniversitySingaporeSingapore

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