Skip to main content
SpringerLink
Log in

Visualizing and Quantifying Acute Inflammation Using ICAM-1 Specific Nanoparticles and MRI Quantitative Susceptibility Mapping

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

As intense and prolonged inflammation correlates with the progression of various inflammatory diseases, locating specific regions of the body with dysregulated levels of inflammation could provide crucial information for effective medical diagnosis and treatment. In this study, we demonstrate high resolution spatiotemporal imaging of inflammation in mice treated with systemic injection of lipopolysaccharides (LPS) to mimic systemic inflammatory response or sepsis. Diagnosis of organ-level inflammation was achieved by magnetic resonance imaging (MRI) of inflammation-sensitive superparamagnetic iron oxide (SPIO)-based nanomicelle termed leukocyte-mimetic nanoparticle (LMN), designed to preferentially localize to cells with inflammation-induced overexpression of intercellular adhesion molecule (ICAM)-1. Using a novel MRI quantitative susceptibility mapping (QSM) technique for non-invasive quantification of SPIO nanoparticles, we observed greater accumulation of LMN in the liver, specific to ICAM-1 induction due to LPS-induced inflammation. However, the accumulation of nanoparticles into the spleen appeared to be due to an ICAM-1 independent, phagocytic activity, resulting in higher levels of both LMN and control nanoparticles in the spleen of LPS-treated than untreated mice. Overall, the amounts of nanoparticles in liver and spleen estimated by QSM were in a good agreement with the values directly measured by radioactivity, presenting an idea that spatiotemporal mapping of LMN by MRI QSM may provide a reliable, rapid, non-invasive method for identifying organ-specific inflammation not offered by existing diagnostic techniques.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777, 2003.

    Article  PubMed  CAS  Google Scholar 

  2. Almenar-Queralt, A., A. Duperray, L. A. Miles, J. Felez, and D. C. Altieri. Apical topography and modulation of ICAM-1 expression on activated endothelium. Am. J. Pathol. 147(5):1278–1288, 1995.

    PubMed  CAS  Google Scholar 

  3. Angus, D. C., W. T. Linde-Zwirble, J. Lidicker, G. Clermont, J. Carcillo, and M. R. Pinsky. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 29(7):1303–1310, 2001.

    Article  PubMed  CAS  Google Scholar 

  4. Barnes, P. J. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol. 8(3):183–192, 2008.

    Article  PubMed  CAS  Google Scholar 

  5. Billiar, T. R., M. A. West, B. J. Hyland, and R. L. Simmons. Splenectomy alters Kupffer cell response to endotoxin. Arch. Surg. 123(3):327–332, 1988.

    Article  PubMed  CAS  Google Scholar 

  6. Buckley, C. D., D. Pilling, J. M. Lord, A. N. Akbar, D. Scheel-Toellner, and M. Salmon. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 22(4):199–204, 2001.

    Article  PubMed  CAS  Google Scholar 

  7. Burns, A. R., F. Takei, and C. M. Doerschuk. Quantitation of ICAM-1 expression in mouse lung during pneumonia. J. Immunol. 153(7):3189–3198, 1994.

    PubMed  CAS  Google Scholar 

  8. Chen, X., R. Wong, I. Khalidov, A. Y. Wang, J. Leelawattanachai, Y. Wang, and M. M. Jin. Inflamed leukocyte-mimetic nanoparticles for molecule imaging of inflammation. Biomaterials 32(30):7651–7661, 2011.

    Article  PubMed  CAS  Google Scholar 

  9. Corti, R., R. Hutter, J. J. Badimon, and V. Fuster. Evolving concepts in the triad of atherosclerosis, inflammation and thrombosis. J. Thromb. Thrombolysis 17(1):35–44, 2004.

    Article  PubMed  CAS  Google Scholar 

  10. Coussens, L. M., and Z. Werb. Inflammation and cancer. Nature 420(6917):860–867, 2002.

    Article  PubMed  CAS  Google Scholar 

  11. Deitch, E. A. Multiple organ failure. Pathophysiology and potential future therapy. Ann. Surg. 216(2):117–134, 1992.

    Article  PubMed  CAS  Google Scholar 

  12. Denis, M. C., U. Mahmood, C. Benoist, D. Mathis, and R. Weissleder. Imaging inflammation of the pancreatic islets in type 1 diabetes. Proc. Natl. Acad. Sci. USA 101(34):12634–12639, 2004.

    Article  PubMed  CAS  Google Scholar 

  13. Dustin, M. L., R. Rothlein, A. K. Bhan, C. A. Dinarello, and T. A. Springer. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J. Immunol. 137(1):245–254, 1986.

    PubMed  CAS  Google Scholar 

  14. Eniola, A. O., and D. A. Hammer. Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes II: effect of degradation on targeting activity. Biomaterials 26(6):661–670, 2005.

    Article  PubMed  CAS  Google Scholar 

  15. Eniola, A. O., P. J. Willcox, and D. A. Hammer. Interplay between rolling and firm adhesion elucidated with a cell-free system engineered with two distinct receptor-ligand pairs. Biophys. J. 85(4):2720–2731, 2003.

    Article  PubMed  CAS  Google Scholar 

  16. Essani, N. A., M. A. Fisher, A. Farhood, A. M. Manning, C. W. Smith, and H. Jaeschke. Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology 21(6):1632–1639, 1995.

    PubMed  CAS  Google Scholar 

  17. Farhood, A., G. M. McGuire, A. M. Manning, M. Miyasaka, C. W. Smith, and H. Jaeschke. Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver. J. Leukoc. Biol. 57(3):368–374, 1995.

    PubMed  CAS  Google Scholar 

  18. Haun, J. B., and D. A. Hammer. Quantifying nanoparticle adhesion mediated by specific molecular interactions. Langmuir 24(16):8821–8832, 2008.

    Article  PubMed  CAS  Google Scholar 

  19. Holme, P. A., U. Orvim, M. J. Hamers, N. O. Solum, F. R. Brosstad, R. M. Barstad, and K. S. Sakariassen. Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis. Arterioscler. Thromb. Vasc. Biol. 17(4):646–653, 1997.

    Article  PubMed  CAS  Google Scholar 

  20. Hu, X., S. Kang, X. Chen, C. B. Shoemaker, and M. M. Jin. Yeast surface two-hybrid for quantitative in vivo detection of protein–protein interactions via the secretory pathway. J. Biol. Chem. 284(24):16369–16376, 2009.

    Article  PubMed  CAS  Google Scholar 

  21. Jaffer, F. A., C. H. Tung, J. J. Wykrzykowska, N. H. Ho, A. K. Houng, G. L. Reed, and R. Weissleder. Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. Circulation 110(2):170–176, 2004.

    Article  PubMed  CAS  Google Scholar 

  22. Jin, M., G. Song, C. V. Carman, Y. S. Kim, N. S. Astrof, M. Shimaoka, D. K. Wittrup, and T. A. Springer. Directed evolution to probe protein allostery and integrin I domains of 200,000-fold higher affinity. Proc. Natl. Acad. Sci. USA 103(15):5758–5763, 2006.

    Article  PubMed  CAS  Google Scholar 

  23. Kang, S., T. Park, X. Chen, G. Dickens, B. Lee, K. Lu, N. Rakhilin, S. Daniel, and M. M. Jin. Tunable physiologic interactions of adhesion molecules for inflamed cell-selective drug delivery. Biomaterials 32(13):3487–3498, 2011.

    Article  PubMed  CAS  Google Scholar 

  24. Lanza, G. M., X. Yu, P. M. Winter, D. R. Abendschein, K. K. Karukstis, M. J. Scott, L. K. Chinen, R. W. Fuhrhop, D. E. Scherrer, and S. A. Wickline. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation 106(22):2842–2847, 2002.

    Article  PubMed  CAS  Google Scholar 

  25. Liu, T., P. Spincemaille, L. de Rochefort, B. Kressler, and Y. Wang. Calculation of susceptibility through multiple orientation sampling (COSMOS): a method for conditioning the inverse problem from measured magnetic field map to susceptibility source image in MRI. Magn. Reson. Med. 61(1):196–204, 2009.

    Article  PubMed  Google Scholar 

  26. Liu, T., P. Spincemaille, L. de Rochefort, R. Wong, M. Prince, and Y. Wang. Unambiguous identification of superparamagnetic iron oxide particles through quantitative susceptibility mapping of the nonlinear response to magnetic fields. Magn. Reson. Imaging 28(9):1383–1389, 2010.

    Article  PubMed  Google Scholar 

  27. Marlin, S. D., and T. A. Springer. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51(5):813–819, 1987.

    Article  PubMed  CAS  Google Scholar 

  28. Massey, J. M., J. Amps, M. S. Viapiano, R. T. Matthews, M. R. Wagoner, C. M. Whitaker, W. Alilain, A. L. Yonkof, A. Khalyfa, N. G. Cooper, J. Silver, and S. M. Onifer. Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp. Neurol. 209(2):426–445, 2008.

    Article  PubMed  CAS  Google Scholar 

  29. McAteer, M. A., A. M. Akhtar, C. von Zur Muhlen, and R. P. Choudhury. An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis 209(1):18–27, 2010.

    Article  PubMed  CAS  Google Scholar 

  30. Muro, S., C. Gajewski, M. Koval, and V. R. Muzykantov. ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs. Blood 105(2):650–658, 2005.

    Article  PubMed  CAS  Google Scholar 

  31. Nahrendorf, M., F. A. Jaffer, K. A. Kelly, D. E. Sosnovik, E. Aikawa, P. Libby, and R. Weissleder. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 114(14):1504–1511, 2006.

    Article  PubMed  CAS  Google Scholar 

  32. Nathan, C. Points of control in inflammation. Nature 420(6917):846–852, 2002.

    Article  PubMed  CAS  Google Scholar 

  33. Nathan, C., and A. Ding. Nonresolving inflammation. Cell 140(6):871–882, 2010.

    Article  PubMed  CAS  Google Scholar 

  34. Nathan, C., and M. Sporn. Cytokines in context. J. Cell Biol. 113(5):981–986, 1991.

    Article  PubMed  CAS  Google Scholar 

  35. Nogueira, N., and Z. A. Cohn. Trypanosoma cruzi: in vitro induction of macrophage microbicidal activity. J. Exp. Med. 148(1):288–300, 1978.

    Article  PubMed  CAS  Google Scholar 

  36. Olanders, K., Z. Sun, A. Borjesson, M. Dib, E. Andersson, A. Lasson, T. Ohlsson, and R. Andersson. The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression, endothelial barrier function, neutrophil tissue influx, and protease inhibitor levels in rats. Shock 18(1):86–92, 2002.

    Article  PubMed  Google Scholar 

  37. Omolola Eniola, A., and D. A. Hammer. In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors. Biomaterials 26(34):7136–7144, 2005.

    Article  PubMed  CAS  Google Scholar 

  38. Panes, J., M. A. Perry, D. C. Anderson, A. Manning, B. Leone, G. Cepinskas, C. L. Rosenbloom, M. Miyasaka, P. R. Kvietys, and D. N. Granger. Regional differences in constitutive and induced ICAM-1 expression in vivo. Am J Physiol 269(6 Pt 2):H1955–H1964, 1995.

    PubMed  CAS  Google Scholar 

  39. Park, S., S. Kang, A. J. Veach, Y. Vedvyas, R. Zarnegar, J. Y. Kim, and M. M. Jin. Self-assembled nanoplatform for targeted delivery of chemotherapy agents via affinity-regulated molecular interactions. Biomaterials 31(30):7766–7775, 2010.

    Article  PubMed  CAS  Google Scholar 

  40. Swirski, F. K., M. Nahrendorf, M. Etzrodt, M. Wildgruber, V. Cortez-Retamozo, P. Panizzi, J. L. Figueiredo, R. H. Kohler, A. Chudnovskiy, P. Waterman, E. Aikawa, T. R. Mempel, P. Libby, R. Weissleder, and M. J. Pittet. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616, 2009.

    Article  PubMed  CAS  Google Scholar 

  41. Van Snick, J. Interleukin-6: an overview. Annu. Rev. Immunol. 8:253–278, 1990.

    Article  PubMed  Google Scholar 

  42. Volpes, R., J. J. van den Oord, and V. J. Desmet. Immunohistochemical study of adhesion molecules in liver inflammation. Hepatology 12(1):59–65, 1990.

    Article  PubMed  CAS  Google Scholar 

  43. Wellen, K. E., and G. S. Hotamisligil. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Invest. 112(12):1785–1788, 2003.

    PubMed  CAS  Google Scholar 

  44. Werner, J., K. Z’Graggen, C. Fernandez-del Castillo, K. B. Lewandrowski, C. C. Compton, and A. L. Warshaw. Specific therapy for local and systemic complications of acute pancreatitis with monoclonal antibodies against ICAM-1. Ann. Surg. 229(6):834–840, 1999, discussion 841–832.

    Google Scholar 

  45. Wilson, M. S., and T. A. Wynn. Pulmonary fibrosis: pathogenesis, etiology and regulation. Mucosal Immunol. 2(2):103–121, 2009.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Support for this work was provided in part by NSF GK-12 Fellowship and American Heart Association Scientist Development Grant (M.M.J.).

Conflict of interest

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA

    Richard Wong, Xiaoyue Chen, Yi Wang, Xuebo Hu & Moonsoo M. Jin

  2. Department of Radiology, Weill Cornell Medical College, New York, NY, 10022, USA

    Richard Wong, Yi Wang & Moonsoo M. Jin

Authors
  1. Richard Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyue Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuebo Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Moonsoo M. Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Moonsoo M. Jin.

Additional information

Associate Editor Jong Hwan Sung oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (MP4 7940 kb)

Supplementary material 2 (MP4 7670 kb)

Supplementary material 1 (DOC 13 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, R., Chen, X., Wang, Y. et al. Visualizing and Quantifying Acute Inflammation Using ICAM-1 Specific Nanoparticles and MRI Quantitative Susceptibility Mapping. Ann Biomed Eng 40, 1328–1338 (2012). https://doi.org/10.1007/s10439-011-0482-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10439-011-0482-3

Keywords

Search

Navigation