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

  • Reshmi Rajendran (a1), John A. Ronald (a2), Tao Ye (a1), Ren Minqin (a1), John W. Chen (a3), Ralph Weissleder (a3), Brian K. Rutt (a2), Barry Halliwell (a4) and Frank Watt (a1)...

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.

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Corresponding author

Corresponding author. E-mail: reshmi_rajendran@sbic.a-star.edu.sg

References

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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), 334339.
Bellin, M.F. (2006). MR contrast agents, the old and the new. Eur J Radiol 60, 314323.
Brasch, R.C. (1992). New directions in the development of MR imaging contrast media. Radiology 183, 1111.
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), 1858418589.
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.
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), 176180.
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, 473481.
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), 95104.
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), 105141.
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, 563576.
Johansson, S.A.E., Campbell, J.L. & Malmqvist, K.G. (1995). Particle Induced X-Ray Emission Spectrometry (PIXE). Chichester, U.K.: John Wiley & Sons.
Maxwell, J.A., Campbell, J.L. & Tesdale, W.J. (1989). The Guelph PIXE software package. Nucl. Instrum Methods B 43, 218.
Mayer, M. (1997). Simnra Users' Guide. Technical Report IPP 9/113, Max-Planck Institut for Plasmaphysik, Garching, Germany.
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), 120129.
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), 11531160.
Querol, M., Chen, J.W. & Bogdanov, A.A. Jr. (2006). A paramagnetic contrast agent with myeloperoxidase-sensing properties. Org Biomol Chem 4(10), 18871895.
Querol, M., Chen, J.W., Weissleder, R. & Bogdanov, A. Jr. (2005). DTPA-bisamide-based MR sensor agents for peroxidase imaging. Org Lett 7(9), 17191722.
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), 5561.
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, 10101019.
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, 291305.
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), 740755.
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), 9195.
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, 646652.
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, 1420.

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

  • Reshmi Rajendran (a1), John A. Ronald (a2), Tao Ye (a1), Ren Minqin (a1), John W. Chen (a3), Ralph Weissleder (a3), Brian K. Rutt (a2), Barry Halliwell (a4) and Frank Watt (a1)...

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