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MR contrast probes that trace gene transcripts for cerebral ischemia in live animals

Christina H. Liu^*,,,1, Shuning Huang^*,, Jiankun Cui^,2, Young R. Kim^*,, Christian T. Farrar^*,, Michael A. Moskowitz, Bruce R. Rosen^*, and Philip K. Liu^,

^* AA Martinos Center for Biomedical Imaging;

NeuroRepair Laboratory/NeuroRadiology Division;

Department of Radiology Massachusetts General Hospital, Charlestown, Massachusetts, USA; and

Harvard-MIT Division of Health Sciences and Techonology Cambridge, Massachusetts, USA

¹Correspondence: Massachusetts General Hospital, 149 13^th St., Rm. 2410, Charlestown, MA 02129, USA. E-mail: philipl{at}nmr.mgh.harvard.edu

The aim of this research was to validate transcription magnetic resonance (MR) imaging (MRI) for gene transcript targeting in acute neurological disorders in live subjects. We delivered three MR probe variants with superparamagnetic iron oxide nanoparticles (SPION, a T₂ susceptibility agent) linked to a phosphorothioate-modified oligodeoxynucleotide (sODN) complementary to c-fos mRNA (SPION-cfos) or ß-actin mRNA (SPION-ß-actin) and to sODN with random sequence (SPION-Ran). Each probe (1 µg Fe in 2 µl) was delivered via intracerebroventricular infusion to the left cerebral ventricle of male C57Black6 mice. We demonstrated SPION retention, measured as decreased T₂* signal or increased R₂* value (R₂*=1/T₂*). Animals that received the SPION-ß-actin probe exhibited the highest R₂* values, followed (in descending order) by SPION-cfos and SPION-Ran. SPION-cfos retention was localized in brain regions where SPION-cfos was present and where hybrids of SPION-cfos and its target c-fos mRNA were detected by in situ reverse transcription PCR. In animals that experienced cerebral ischemia, SPION-cfos retention was significantly increased in locations where c-fos mRNA increased in response to the ischemic insult; these elevations were not observed for SPION-ß-actin and SPION-Ran. This study should enable MR detection of mRNA alteration in disease models of the central nervous system. —Liu, C. H., Huang, S., Cui, J., Kim, Y. R., Farrar, C. T., Moskowitz, M. A., Rosen. B. R., Liu, P. K. MR contrast probes that trace gene transcripts for cerebral ischemia in live animals.

Key Words: cardiac arrest • immediate early genes • oxidative stress • nanotechnology • signal transduction

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				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]