title: Cell-permeable MR contrast agents with increased intracellular retention.
abstract: Magnetic resonance imaging (MRI) is a technique used in both clinical and experimental settings to produce high-resolution images of opaque organisms without ionizing radiation. Currently, MR imaging is augmented by contrast agents, and the vast majority these small molecule Gd(III) chelates are confined to the extracellular regions. As a result, contrast agents are confined to vascular regions reducing their ability to provide information about cell physiology or molecular pathology. We have shown that polypeptides of arginine have the capacity to transport Gd(III) contrast agents across cell membranes. However, this transport is not unidirectional, and once inside the cell, the arginine-modified contrast agents efflux rapidly, decreasing the intracellular Gd(III) concentration and corresponding MR image intensity. By exploiting the inherent disulfide reducing environment of cells, thiol compounds, Gd(III)-DOTA-SS-Arg 8 and Gd(III)-DTPA-SS-Arg 8, are cleaved from their cell-penetrating peptide transduction domains upon cell internalization. This reaction prolongs the cell-associated lifetime of the chelated Gd(III) by cleaving it from the cell transduction domain.
authors.affiliation: Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Endres
authors.forename: Keith W
authors.initials: KW
authors.lastname: MacRenaris
authors.forename: Stefan
authors.initials: S
authors.lastname: Vogt
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Meade
mesh_terms: D000818:Animals; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry; D003287:Contrast Media / Q000138:chemical synthesis / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry; D042541:Intracellular Space / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000378:metabolism*; D010539:Permeability; D017356:Synchrotrons; D014965:X-Rays
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D004220:Disulfides; D009942:Organometallic Compounds; D005682:Gadolinium