title: Noninvasive delivery of gene targeting probes to live brains for transcription MRI.
abstract: We aimed to test the feasibility of detecting gliosis in living brains when the blood-brain barrier (BBB) is disrupted. We designed a novel magnetic resonance (MR) probe that contains superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility contrast agent) linked to a short DNA sequence complementary to the cerebral mRNA of glial fibrillary acidic protein (GFAP) found in glia and astrocytes. As a control, we also used a sequence complementary to the mRNA of beta-actin. Our objectives are to demonstrate that this new probe, SPION-gfap, could be delivered to the brain when administered by eyedrop solution to the conjunctival sac. We induced BBB leakage by puncture wound, global cerebral ischemia, and cortical spreading depression in C57BL6 mice; 1 day after probe delivery we acquired T2* MR images and R2* (R2* = 1/T2*) maps using a transcription MRI technique in live mice. We found that the SPION-gfap probe reported foci with elevated signal in subtraction R2* maps and that these foci matched areas identified as having extensive glial network (gliosis) in postmortem immunohistochemistry. Similarly, animals administered the control probe exhibited foci of R2* elevation that matched beta-actin-expressing endothelia in the vascular wall. We conclude that our modular MR probe, delivered in an eyedrop solution, effectively reports gliosis associated with acute neurological disorders in living animals. As BBB leakage is often observed in acute neurological disorders, this study also served to validate noninvasive delivery of MR probes to the brains of live animals after acute neurological disorders.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Liu
authors.forename: Zerong
authors.initials: Z
authors.lastname: You
authors.forename: JiaQian
authors.initials: J
authors.lastname: Ren
authors.forename: Young R
authors.initials: YR
authors.lastname: Kim
authors.forename: Katharina
authors.initials: K
authors.lastname: Eikermann-Haerter
authors.forename: Philip K
authors.initials: PK
authors.lastname: Liu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology; D003287:Contrast Media / Q000008:administration & dosage*; D005290:Ferric Compounds / Q000008:administration & dosage*; D018390:Gene Targeting; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000175:diagnosis*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D014158:Transcription, Genetic
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; D005904:Glial Fibrillary Acidic Protein; D009838:Oligodeoxyribonucleotides; C000499:ferric oxide