, Volume 4, Issue 1, pp 59–70 | Cite as

Magnetic Resonance Imaging for Monitoring of Magnetic Polyelectrolyte Capsule In Vivo Delivery

  • Qiangying Yi
  • Danyang Li
  • Bingbing Lin
  • Anton M. Pavlov
  • Dong Luo
  • Qiyong Gong
  • Bin Song
  • Hua AiEmail author
  • Gleb B. SukhorukovEmail author


Layer-by-layer (LbL) assembled polyelectrolyte capsules have been widely studied as promising delivery systems due to their well-controlled architectures. Although their potential applications in vitro have been widely investigated, at present, it is still a challenging task to track their real-time delivery in vivo, where and how they would be located following their administration. In this work, the noninvasive magnetic resonance imaging (MRI) technique was applied to monitor the delivery of polyelectrolyte capsules in vivo, incorporating magnetite nanoparticles as imaging components. First, MRI scan was performed over 6 h after sample administration at the magnetic field of 3.0 T; magnetic capsules, both poly(allylamine hydrochloride)/poly(styrenesulfonate sodium salt)-based and poly-l-arginine hydrochloride/dextran sulfate (Parg/DS)-based, were detected mostly in the liver region, where the transverse relaxation time (T2) was shortened and hypointense images were visualized, demonstrating a contrast-enhanced MRI effect between liver and adjacent tissue. A continuous MRI scan found that the contrast-enhanced MRI effect can last up to 30 h; in the mean time, the Parg/DS-based capsules with smaller diameter were found to have a pronounced clearance effect, which resulted in a weakened MRI effect in the liver. No obvious toxicity was found in animal studies, and all mice survived after MRI scans. Histology study provided evidences to support the MRI results, and also revealed the destination of these magnetic capsules over 30 h after administration.


Magnetite Capsule MRI Liver Spleen 



The authors thank the Radiology Department of West China Hospital (Sichuan University, China) for the support on the MRI measurement. The authors also acknowledge the National Natural Science Foundation of China (NSFC 51173117) and National Key Basic Research Program of China (2013CB933903) for the financial support. This research was supported by an EPSRC “Global Engagement” grant to establish research links between Queen Mary University of London, and Sichuan University.


  1. 1.
    Stuart, M. A. C., Huck, W. T. S., Genzer, J., Müller, M., Ober, C., Stamm, M., et al. (2010). Emerging applications of stimuli-responsive polymer materials. Nature Materials, 9, 101–113.CrossRefGoogle Scholar
  2. 2.
    Delcea, M., Möhwald, H., Skirtach, A. G. (2011). Stimuli-responsive LbL capsules and nanoshells for drug delivery. Advanced Drug Delivery Reviews, 63, 730–747.CrossRefGoogle Scholar
  3. 3.
    del Mercato, L., Rivera-Gil, P., Abbasi, A. Z., Ochs, M., Ganas, C., Zins, I., et al. (2010). LbL multilayer capsules: recent progress and future outlook for their use in life sciences. Nanoscale, 2, 458–467.CrossRefGoogle Scholar
  4. 4.
    Klitzing, R. (2006). Internal structure of polyelectrolyte multilayer assemblies. Physical Chemistry Chemical Physics, 8, 5012–5033.CrossRefGoogle Scholar
  5. 5.
    Skirtach, A. G., Yashchenok, A. M., Möhwald, H. (2011). Encapsulation, release and applications of LbL polyelectrolyte multilayer capsules. Chemical Communication, 47, 12736–12746.CrossRefGoogle Scholar
  6. 6.
    Ariga, K., Lvov, Y. M., Kawakami, K., Ji, Q., Hill, J. P. (2011). Layer-by-layer self-assembled shells for drug delivery. Advanced Drug Delivery Reviews, 14, 762–771.CrossRefGoogle Scholar
  7. 7.
    De Koker, S., Hoogenboom, R., De Geest, B. G. (2012). Polymeric multilayer capsules for drug delivery. Chemical Society Reviews, 41, 2867–2884.CrossRefGoogle Scholar
  8. 8.
    De Koker, S., De Cock, L. J., Rivera-Gil, P., Parak, W. J., Auzély Velty, R., Vervaet, C., et al. (2011). Polymeric multilayer capsules delivering biotherapeutics. Advanced Drug Delivery Reviews, 63, 748–761.CrossRefGoogle Scholar
  9. 9.
    De Geest, B. G., De Koker, S., Sukhorukov, G. B., Kreft, O., Parak, W. J., Skirtach, A. G., et al. (2009). Polyelectrolyte microcapsules for biomedical applications. Soft Matter, 5, 82–291.CrossRefGoogle Scholar
  10. 10.
    Brown, M. A., & Semelka, R. C. (2011). MRI: basic principles and applications. Portland: Wiley.Google Scholar
  11. 11.
    Modo, M. M., & Bulte, J. W. (2007). Molecular and cellular MR imaging. Boca Raton: CRC.CrossRefGoogle Scholar
  12. 12.
    Sheparovych, R., Sahoo, Y., Motornov, M., Wang, S., Luo, H., Prasad, P. N., et al. (2006). Polyelectrolyte stabilized nanowires from Fe3O4 nanoparticles via magnetic field induced self-assembly. Chemistry of Materials, 18, 591–593.CrossRefGoogle Scholar
  13. 13.
    Semelka, R. C., & Helmberger, T. K. (2001). Contrast agents for MR imaging of the liver. Radiology, 218, 27–38.CrossRefGoogle Scholar
  14. 14.
    Moffat, B. A., Reddy, G. R., McConville, P., Hall, D. E., Chenevert, T. L., Kopelman, R. R., et al. (2003). A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI. Molecular Imaging, 2, 324–332.CrossRefGoogle Scholar
  15. 15.
    Na, H. B., Song, I. C., Hyeon, T. (2009). Inorganic nanoparticles for MRI contrast agents. Advanced Materials, 21, 2133–2148.CrossRefGoogle Scholar
  16. 16.
    Andrews, N. C. (1999). Disorders of iron metabolism. New England Journal of Medicine, 341, 1986–1995.CrossRefGoogle Scholar
  17. 17.
    Hentze, M. W., Muckenthaler, M. U., Andrews, N. C. (2004). Balancing acts: molecular control of mammalian iron metabolism. Cell, 117, 285–297.CrossRefGoogle Scholar
  18. 18.
    Nune, S. K., Gunda, P., Thallapally, P. K., Lin, Y. Y., Forrest, M. L., Berkland, C. J. (2009). Nanoparticles for biomedical imaging. Expert Opinion on Drug Delivery, 6, 1175–1194.CrossRefGoogle Scholar
  19. 19.
    De Cock, L. J., De Koker, S., De Geest, B. G., Grooten, J., Vervaet, C., Remon, J. P., et al. (2010). Polymeric multilayer capsules in drug delivery. Angewandte Chemie International Edition, 49, 6954–6973.CrossRefGoogle Scholar
  20. 20.
    Sukhorukov, G. B., Volodkin, D. V., Günther, A. M., Petrov, A. I., Shenoy, D. B., Möhwald, H. (2004). Porous calcium carbonate microparticles as templates for encapsulation of bioactive compounds. Journal of Materials Chemistry, 14, 2073–2081.CrossRefGoogle Scholar
  21. 21.
    Gorin, D. A., Portnov, S. A., Inozemtseva, O. A., Luklinska, Z., Yashchenok, A. M., Pavlov, A. M., et al. (2008). Magnetic/gold nanoparticle functionalized biocompatible microcapsules with sensitivity to laser irradiation. Physical Chemistry Chemical Physics, 10, 6899–6905.CrossRefGoogle Scholar
  22. 22.
    Köhler, K., & Sukhorukov, G. B. (2007). Heat treatment of polyelectrolyte multilayer capsules: a versatile method for encapsulation. Advanced Functional Materials, 17, 2053–2061.CrossRefGoogle Scholar
  23. 23.
    Pavlov, A.M. (2012). Multilayer microcapsules for delivery, control and triggered release of bioactive compounds. (Unpublished dissertation). Queen Mary University of London, LondonGoogle Scholar
  24. 24.
    Berret, J. F., Schonbeck, N., Gazeau, F., El Kharrat, D., Sandre, O., Vacher, A., et al. (2006). Controlled clustering of superparamagnetic nanoparticles using block copolymers: design of new contrast agents for magnetic resonance imaging. Journal of the American Chemical Society, 128, 1755–1761.CrossRefGoogle Scholar
  25. 25.
    Zhu, Y., Shi, J., Shen, W., Dong, X., Feng, J., Ruan, M., et al. (2005). Stimuli-responsive controlled drug release from a hollow mesoporous silica sphere/polyelectrolyte multilayer core–shell structure. Angewandte Chemie, 117, 5213–5217.CrossRefGoogle Scholar
  26. 26.
    Déjugnat, C., & Sukhorukov, G. B. (2004). pH-responsive properties of hollow polyelectrolyte microcapsules templated on various cores. Langmuir, 20, 7265–7269.CrossRefGoogle Scholar
  27. 27.
    Städler, B., Price, A. D., Zelikin, A. N. (2011). A critical look at multilayered polymer capsules in biomedicine: drug carriers, artificial organelles, and cell mimics. Advanced Functional Materials, 21, 14–28.CrossRefGoogle Scholar
  28. 28.
    De Geest, B. G., Vandenbroucke, R. E., Guenther, A. M., Sukhorukov, G. B., Hennink, W. E., Sanders, N. N., et al. (2006). Intracellularly degradable polyelectrolyte microcapsules. Advanced Materials, 18, 1005–1009.CrossRefGoogle Scholar
  29. 29.
    De Koker, S., De Geest, B. G., Singh, S. K., De Rycke, R., Naessens, T., Van Kooyk, Y., et al. (2009). Polyelectrolyte microcapsules as antigen delivery vehicles to dendritic cells: uptake, processing, and cross-presentation of encapsulated antigens. Angewandte Chemie, 121, 8637–8641.CrossRefGoogle Scholar
  30. 30.
    Moghimi, S. M., Hunter, A. C., Murray, J. C. (2001). Long-circulating and target-specific nanoparticles: theory to practice. Pharmacological Reviews, 53, 283–318.Google Scholar
  31. 31.
    Edwards, D. A., Hanes, J., Caponetti, G., Hrkach, J., Ben-Jebria, A., Eskew, M. L., et al. (1997). Large porous particles for pulmonary drug delivery. Science, 276, 1868–1872.CrossRefGoogle Scholar
  32. 32.
    Köhler, K., Shchukin, D. G., Möhwald, H., Sukhorukov, G. B. (2005). Thermal behavior of polyelectrolyte multilayer microcapsules. 1. The effect of odd and even layer number. The Journal of Physical Chemistry. B, 109, 18250–18259.CrossRefGoogle Scholar
  33. 33.
    Leporatti, S., Gao, C., Voigt, A., Donath, E., Möhwald, H. (2001). Shrinking of ultrathin polyelectrolyte multilayer capsules upon annealing: a confocal laser scanning microscopy and scanning force microscopy study. The European Physical Journal E, 5, 13–20.CrossRefGoogle Scholar
  34. 34.
    Zhang, R., Köhler, K., Kreft, O., Skirtach, A., Möhwald, H., Sukhorukov, G. B. (2010). Salt-induced fusion of microcapsules of polyelectrolytes. Soft Matter, 6, 4742–4747.CrossRefGoogle Scholar
  35. 35.
    Ai, H. (2011). Layer-by-layer capsules for magnetic resonance imaging and drug delivery. Advanced Drug Delivery Reviews, 63, 772–788.CrossRefGoogle Scholar
  36. 36.
    Wang, Y. X., Hussain, S. M., Krestin, G. P. (2001). Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging. European Radiology, 11, 2319–2331.CrossRefGoogle Scholar
  37. 37.
    Corot, C., Robert, P., Idée, J.-M., Port, M. (2006). Recent advances in iron oxide nanocrystal technology for medical imaging. Advanced Drug Delivery Reviews, 58, 1471–1504.CrossRefGoogle Scholar
  38. 38.
    Lu, J., Ma, S., Sun, J., Xia, C., Liu, C., Wang, Z., et al. (2009). Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging. Biomaterials, 30, 2919–2928.CrossRefGoogle Scholar
  39. 39.
    Mikhaylov, G., Mikac, U., Magaeva, A. A., Itin, V. I., Naiden, E. P., Psakhye, I., et al. (2011). Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment. Nature Nanotechnology, 6, 594–602.CrossRefGoogle Scholar
  40. 40.
    Liu, G., Wang, Z., Lu, J., Xia, C., Gao, F., Gong, Q., et al. (2011). Low molecular weight alkyl-polycation wrapped magnetite nanoparticle clusters as MRI probes for stem cell labeling and in vivo imaging. Biomaterials, 32, 528–537.CrossRefGoogle Scholar
  41. 41.
    Xie, J., Liu, G., Eden, H. S., Ai, H., Chen, X. (2011). Surface-engineered magnetic nanoparticle platforms for cancer imaging and therapy. Accounts of Chemical Research, 44, 883–892.CrossRefGoogle Scholar
  42. 42.
    Knoblaugh, S., Randolph-Habeckers, J., Rath, S. (2012). Necropsy and histology. In P. Treuting & S. M. Dintzis (Eds.), Comparative anatomy and histology: a mouse and human atlas (1st ed., p. 23). Oxford: Elsevier.Google Scholar
  43. 43.
    Torchilin, V. P. (2006). Multifunctional nanocarriers. Advanced Drug Delivery Reviews, 58, 1532–1555.CrossRefGoogle Scholar
  44. 44.
    Ai, H., Pink, J. J., Shuai, X., Boothman, D. A., Gao, J. (2005). Interactions between self-assembled polyelectrolyte shells and tumor cells. Journal of Biomedical Materials Research, Part A, 73, 303–312.CrossRefGoogle Scholar
  45. 45.
    Brigger, I., Dubernet, C., Couvreur, P. (2002). Nanoparticles in cancer therapy and diagnosis. Advanced Drug Delivery Reviews, 54, 631–651.CrossRefGoogle Scholar
  46. 46.
    Heuberger, R., Sukhorukov, G. B., Vörös, J., Textor, M., Möhwald, H. (2005). Biofunctional polyelectrolyte multilayers and microcapsules: control of non-specific and bio-specific protein adsorption. Advanced Functional Materials, 15, 357–366.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Qiangying Yi
    • 1
  • Danyang Li
    • 2
  • Bingbing Lin
    • 2
  • Anton M. Pavlov
    • 1
  • Dong Luo
    • 2
  • Qiyong Gong
    • 3
  • Bin Song
    • 3
  • Hua Ai
    • 2
    • 3
    Email author
  • Gleb B. Sukhorukov
    • 1
    Email author
  1. 1.School of Engineering and Materials ScienceQueen Mary University of LondonLondonUK
  2. 2.National Engineering Research Centre for BiomaterialsSichuan UniversityChengduPeople’s Republic of China
  3. 3.Department of Radiology, West China HospitalSichuan UniversityChengduPeople’s Republic of China

Personalised recommendations