Hostname: page-component-cd9895bd7-dk4vv Total loading time: 0 Render date: 2024-12-27T19:30:46.976Z Has data issue: false hasContentIssue false
  • English
  • Français

Nuclear Microscopy: A Novel Technique for Quantitative Imaging of Gadolinium Distribution within Tissue Sections

Published online by Cambridge University Press:  03 July 2009

Reshmi Rajendran ,
John A. Ronald ,
Tao Ye ,
Ren Minqin ,
John W. Chen ,
Ralph Weissleder ,
Brian K. Rutt ,
Barry Halliwell  and
Frank Watt
Reshmi Rajendran*
Affiliation:
Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore
John A. Ronald
Affiliation:
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
Tao Ye
Affiliation:
Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore
Ren Minqin
Affiliation:
Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore
John W. Chen
Affiliation:
Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
Ralph Weissleder
Affiliation:
Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
Brian K. Rutt
Affiliation:
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
Barry Halliwell
Affiliation:
Department of Biochemistry, National University of Singapore, Singapore
Frank Watt
Affiliation:
Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore
*
Corresponding author. E-mail: [email protected]
Get access

Abstract

All clinically-approved and many novel gadolinium (Gd)-based contrast agents used to enhance signal intensity in magnetic resonance imaging (MRI) are optically silent. To verify MRI results, a “gold standard” that can map and quantify Gd down to the parts per million (ppm) levels is required. Nuclear microscopy is a relatively new technique that has this capability and is composed of a combination of three ion beam techniques: scanning transmission ion microscopy, Rutherford backscattering spectrometry, and particle induced X-ray emission used in conjunction with a high energy proton microprobe. In this proof-of-concept study, we show that in diseased aortic vessel walls obtained at 2 and 4 h after intravenous injection of the myeloperoxidase-senstitive MRI agent, bis-5-hydroxytryptamide-diethylenetriamine-pentaacetate gadolinium, there was a time-dependant Gd clearance (2 h = 18.86 ppm, 4 h = 8.65 ppm). As expected, the control animal, injected with the clinically-approved conventional agent diethylenetriamine-pentaacetate gadolinium and sacrificed 1 week after injection, revealed no significant residual Gd in the tissue. Similar to known in vivo Gd pharmacokinetics, we found that Gd concentration dropped by a factor of 2 in vessel wall tissue in 1.64 h. Further high-resolution studies revealed that Gd was relatively uniformly distributed, consistent with random agent diffusion. We conclude that nuclear microscopy is potentially very useful for validation studies involving Gd-based magnetic resonance contrast agents.

Keywords

gadoliniummagnetic resonance imagingnuclear microscopyPIXESTIMRBSatherosclerosis
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 15 , Issue 4 , August 2009 , pp. 338 - 344
Copyright
Copyright © Microscopy Society of America 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Baker, J.F., Kratz, L.C., Stevens, G.R. & Wible, J.H. Jr. (2004). Pharmacokinetics and safety of the MRI contrast agent gadoversetamide injection (OptiMARK) in healthy pediatric subjects. Invest Radiol 39(6), 334–339.CrossRefGoogle ScholarPubMed
Bellin, M.F. (2006). MR contrast agents, the old and the new. Eur J Radiol 60, 314–323.CrossRefGoogle ScholarPubMed
Brasch, R.C. (1992). New directions in the development of MR imaging contrast media. Radiology 183, 1–111.CrossRefGoogle ScholarPubMed
Breckwoldt, M.O., Chen, J.W., Stangenberg, L., Aikawa, E., Rodriguez, E., Qiu, S., Moskowitz, M.A. & Weissleder, R. (2008). Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci USA 105(47), 18584–18589.CrossRefGoogle ScholarPubMed
Bremerich, J., Colet, J.M., Giovenzana, G.B., Aime, S., Scheffler, K., Laurent, S., Bongartz, G. & Muller, R.N. (2001). Slow clearance gadolinium-based extracellular and intravascular contrast media for three-dimensional MR angiography. J Magn Reson Imaging 13(4), 588–93.CrossRefGoogle ScholarPubMed
Carr, A.C., Myzak, M.C., Stocker, R., McCall, M.R. & Frei, B. (2000). Myeloperoxidase binds to low-density lipoprotein: Potential implications for atherosclerosis. FEBS Lett 487(2), 176–180.CrossRefGoogle ScholarPubMed
Chen, J.W., Sans, M.Q., Bogdanov, A. & Weissleder, R. (2006). Imaging of myeloperoxidase in mice by using novel amplifiable paramagnetic substrates. Radiol 240-242, 473–481.CrossRefGoogle Scholar
Daley, S.J., Herderick, E.E., Cornhill, J.F. & Rogers, K.A. (1994a). Cholesterol-fed and casein-fed rabbit models of atherosclerosis. Part 1: Differing lesion area and volume despite equal plasma cholesterol levels. Arterioscler Thromb 14(1), 95–104.CrossRefGoogle ScholarPubMed
Daley, S.J., Klemp, K.F., Guyton, J.R. & Rogers, K.A. (1994b). Cholesterol-fed and casein-fed rabbit models of atherosclerosis. Part 2: Differing morphological severity of atherogenesis despite matched plasma cholesterol levels. Arterioscler Thromb 14(1), 105–141.CrossRefGoogle ScholarPubMed
Idee, J-M., Port, M., Raynal, I., Schaefer, M., Greneur, S.L. & Corot, C. (2006). Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: A review. Fundam Clin Pharmacol 20, 563–576.CrossRefGoogle ScholarPubMed
Johansson, S.A.E., Campbell, J.L. & Malmqvist, K.G. (1995). Particle Induced X-Ray Emission Spectrometry (PIXE). Chichester, U.K.: John Wiley & Sons.Google Scholar
Maxwell, J.A., Campbell, J.L. & Tesdale, W.J. (1989). The Guelph PIXE software package. Nucl. Instrum Methods B 43, 218.CrossRefGoogle Scholar
Mayer, M. (1997). Simnra Users' Guide. Technical Report IPP 9/113, Max-Planck Institut for Plasmaphysik, Garching, Germany.Google Scholar
Meding, J., Urich, M., Licha, K., Reinhardt, M., Misselwitz, B., Fayad, Z.A. & Weinmann, H.J. (2007). Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M. Contast Media Mol Imag 2(3), 120–129.CrossRefGoogle ScholarPubMed
Nahrendorf, M., Sosnovik, D., Chen, J.W., Panizzi, P., Figueiredo, J.L., Aikawa, E., Libby, P., Swirski, F.K. & Weissleder, R. (2008). Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117(9), 1153–1160.CrossRefGoogle ScholarPubMed
Querol, M., Chen, J.W. & Bogdanov, A.A. Jr. (2006). A paramagnetic contrast agent with myeloperoxidase-sensing properties. Org Biomol Chem 4(10), 1887–1895.CrossRefGoogle ScholarPubMed
Querol, M., Chen, J.W., Weissleder, R. & Bogdanov, A. Jr. (2005). DTPA-bisamide-based MR sensor agents for peroxidase imaging. Org Lett 7(9), 1719–1722.CrossRefGoogle ScholarPubMed
Roijers, R.B., Dutta, R.K., Cleutjens, J.P.M., Mutsaers, P.H.A., de Goeij, J.J.M. & van der Vusse, G.J. (2008). Early calcifications in human coronary arteries as determined with a proton microprobe. Anal Chem 80(1), 55–61.CrossRefGoogle ScholarPubMed
Ronald, J.A., Walcarius, R., Robinson, J.F., Hegele, R.A., Rutt, B.K. & Rogers, K.A. (2007). MRI of early and late-stage arterial remodeling in a low level cholesterol-fed rabbit model of atherosclerosis. J Magn Reson Imaging 26, 1010–1019.CrossRefGoogle Scholar
Strijkers, G.J., Mulder, J.M.W., Van Tilborg, G.A.F. & Nicolay, K. (2007). MRI contrast agents: Current status and future perspectives. Anti-Cancer Agents Med Chem 7, 291–305.CrossRefGoogle ScholarPubMed
Wada, Y., Sugiyama, A., Kohro, T., Kobayashi, M., Takeya, M., Naito, M. & Kodama, T. (2000). In vitro model of atherosclerosis using coculture of arterial wall cells and macrophage. Yonsei Med J 41(6), 740–755.CrossRefGoogle ScholarPubMed
Wasserman, B.A., Casal, C.S., Astor, B.C., Aletras, A.H. & Arai, A.E. (2005). Wash-in kinetics for gadolinium-enhanced magnetic resonance imaging of carotid atheroma. J Magn Reson Imaging 21(1), 91–95.CrossRefGoogle ScholarPubMed
Watt, F., Rajendran, R., Ren, M.Q., Tan, B.K.H. & Halliwell, B. (2006). A nuclear microscopy study of trace elements Ca, Fe, Zn and Cu in atherosclerosis. Nucl Instrum Methods Phys Res B 249, 646–652.CrossRefGoogle Scholar
Watt, F., Van Kan, J.A., Rajta, I., Bettiol, A.A., Choo, T.F., Breese, M.B.H. & Osipowicz, T. (2003). The National University of Singapore high energy ion nano-probe facility: Performance tests. Nucl Instrum Methods Phys Res B 210, 14–20.CrossRefGoogle Scholar