title: Crossing the blood-brain barrier: a potential application of myristoylated polyarginine for in vivo neuroimaging.
abstract: As basic neurological research continues to reveal novel targets for therapy, the need to deliver therapeutic agents across the blood-brain barrier (BBB) becomes increasingly important. If developed, delivery modules would bring targeting molecules across the BBB to their respective active sites. In addition, it would be highly advantageous if the bioavailability of these delivered agents could be monitored over time using non-invasive imaging techniques. Here, we describe a versatile delivery module based on a myristoylated polyarginine backbone, which crosses the BBB. Incorporation of the fatty acid group was achieved using a Schotten-Bauman reaction with quantitative yield, and the peptide was further synthesized by conventional solid phase peptide synthesis (SPPS). We report for the first time the in vivo distribution of the delivery module over time into mouse brain using near-infrared (NIR) fluorescence imaging. The fluorescent cargo was detected in vivo from 24-48 h post IV injection and was further characterized in perfused brains. Immunohistochemical staining of excised brain showed that the delivery module primarily accumulated in neurons with occasional localization in astrocytes and endothelial cells. We conclude that this approach can be used for the delivery of imaging probes and potentially targeted therapeutics across the BBB.
authors.affiliation: MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, USA.
authors.forename: Wellington
authors.initials: W
authors.lastname: Pham
authors.forename: Bing-Qiao
authors.initials: BQ
authors.lastname: Zhao
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
authors.forename: Bruce
authors.initials: B
authors.lastname: Rosen
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D005456:Fluorescent Dyes; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015091:beta-Alanine / Q000737:chemistry
chemical_list: D005227:Fatty Acids; D005456:Fluorescent Dyes; D010455:Peptides; D015091:beta-Alanine; C015462:polyarginine