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The Journal of Neuroscience, January 17, 2007, 27(3):713-722; doi:10.1523/JNEUROSCI.4660-06.2007

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Cellular/Molecular
Imaging Cerebral Gene Transcripts in Live Animals

Christina H. Liu,^1,2,3 Young R. Kim,^1,3 Jia Q. Ren,^1,3 Florian Eichler,⁴ Bruce R. Rosen,^1,3 and Philip K. Liu^2,3

¹Athinoula A. Martinos Center for Biomedical Imaging, ²Transcript Imaging and NeuroRepair Laboratory, ³Department of Radiology, and ⁴Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Philip K. Liu, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Room 2410, Charlestown, MA 02129. Email: philipl{at}nmr.mgh.harvard.edu

To circumvent the limitations of using postmortem brain in molecular assays, we used avidin–biotin binding to couple superparamagnetic iron oxide nanoparticles (SPIONs) (15–20 nm) to phosphorothioate-modified oligodeoxynucleotides (sODNs) with sequence complementary to c-fos and ß-actin mRNA (SPION-cfos and SPION-ßactin, respectively) (14–22 nm). The Stern–Volmer constant for the complex of SPION and fluorescein isothiocyanate (FITC)-sODN is 3.1 x 10⁶/M. We studied the feasibility of using the conjugates for in vivo magnetic resonance imaging (MRI) to monitor gene transcription, and demonstrated that these complexes at 40 µg of Fe per kilogram of body weight were retained at least 1 d after intracerebroventricular infusion into the left ventricle of C57Black6 mice. SPION retention measured by MRI as T₂* or R₂* maps (R₂* = 1/T₂*) was compared with histology of iron oxide (Prussian blue) and FITC-labeled sODN. We observed significant reduction in magnetic resonance (MR) T₂* signal in the right cortex and striatum; retention of SPION-cfos and SPION-ßactin positively correlated with c-fos and ß-actin mRNA maps obtained from in situ hybridization. Histological examination showed that intracellular iron oxide and FITC-sODN correlated positively with in vivo MR signal reduction. Furthermore, in animals that were administered SPION-cfos and amphetamine (4 mg/kg, i.p.), retention was significantly elevated in the nucleus accumbens, striatum, and medial prefrontal cortex of the forebrain. Control groups that received SPION-cfos and saline or that received a SPION conjugate with a random-sequence probe and amphetamine showed no retention. These results demonstrated that SPION-sODN conjugates can detect active transcriptions of specific mRNA species in living animals with MRI.

Key words: amphetamine; antisense delivery; aptamer; drug addiction; gene transcription; immediate-early genes; nanotechnology; signal transduction

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Received July 31, 2006; revised Nov. 30, 2006; accepted Dec. 13, 2006.

Correspondence should be addressed to Dr. Philip K. Liu, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Room 2410, Charlestown, MA 02129. Email: philipl{at}nmr.mgh.harvard.edu

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				P. K. Liu, J. B. Mandeville, Guangping Dai, B. G. Jenkins, Y. R. Kim, and C. H. Liu Transcription MRI: A New View of the Living Brain Neuroscientist, October 1, 2008; 14(5): 503 - 520. [Abstract] [PDF]

				C. H. Liu, Z. You, J. Ren, Y. R. Kim, K. Eikermann-Haerter, and P. K. Liu Noninvasive delivery of gene targeting probes to live brains for transcription MRI FASEB J, April 1, 2008; 22(4): 1193 - 1203. [Abstract] [Full Text] [PDF]

				C. H. Liu, S. Huang, J. Cui, Y. R. Kim, C. T. Farrar, M. A. Moskowitz, B. R. Rosen, and P. K. Liu MR contrast probes that trace gene transcripts for cerebral ischemia in live animals FASEB J, September 1, 2007; 21(11): 3004 - 3015. [Abstract] [Full Text] [PDF]

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