Microscopy and Microanalysis

Biological Applications

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

Reshmi Rajendrana1 c1, John A. Ronalda2, Tao Yea1, Ren Minqina1, John W. Chena3, Ralph Weissledera3, Brian K. Rutta2, Barry Halliwella4 and Frank Watta1

a1 Centre for Ion Beam Applications, Department of Physics, National University of Singapore, Singapore

a2 Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

a3 Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

a4 Department of Biochemistry, National University of Singapore, Singapore

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.

(Received January 23 2009)

(Accepted June 02 2009)

Correspondence:

c1 Corresponding author. E-mail: reshmi_rajendran@sbic.a-star.edu.sg

Footnotes

R.R. and J.A.R. contributed equally to this work.