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Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor Madushani Dharmarwardana, Andre F Martins, Zhuo Chen, Philip Palacios, Chance M Nowak, Raymond P Welch, Shaobo Li, Michael Andrew Luzuriaga, Leonidas Bleris, Brad S. Pierce, A Dean Sherry, and Jeremiah J Gassensmith Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00262 • Publication Date (Web): 17 May 2018 Downloaded from http://pubs.acs.org on May 20, 2018
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Molecular Pharmaceutics
Nitroxyl Modified Tobacco Mosaic Virus as a MetalFree High-Relaxivity MRI and EPR Active Superoxide Sensor MadushaniDharmarwardana,a† André F. Martins,a,e†ZhuoChen,a Philip M. Palacios,d Chance M. Nowak,b Raymond P. Welch,aShaoboLi,a Michael A. Luzuriaga,a Leonidas Bleris,b Brad S. Pierce,d A. Dean Sherry,a,e Jeremiah J. Gassensmitha,c,* a
Department of Chemistry and Biochemistry, bDepartment of Biological Sciences, cDepartment of Bioengineering, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080-3021, USA. dDepartment of Chemistry and Biochemistry, College of Sciences, The University of Texas at Arlington, Arlington, Texas 76019, USA. eAdvanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. KEYWORDS Tobacco mosaic virus, reactive oxygen species, magnetic resonance imaging, electron paramagnetic resonance, bio-conjugation, Organic radical contrast agents
ABSTRACT:Superoxide overproduction is known to occur in multiple disease states requiring critical care yet non-invasive detection of superoxide in deep tissue remains a challenge. Herein, we report a metal-free magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) active contrast agent prepared by “click conjugating” paramagnetic organic radical contrast agents (ORCAs) to the surface of tobacco mosaic virus (TMV). While ORCAs are known to be reduced in vivoto an MRI/EPR silent state, their oxidation is facilitated specifically by reactive oxygen species—in particular superoxide—and are largely unaffected by peroxides and molecular oxygen. Unfortunately, single molecule ORCAs typically offer weak MRI contrast. In contrast, our data confirm that the macromolecular ORCA-TMV conjugates show marked enhancement for T1 contrast at low field (
