Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor

• Published in: Molecular pharmaceutics 2018-08, Vol.15 (8), p.2973-2983
• Main Authors: Dharmarwardana, Madushani, Martins, André F, Chen, Zhuo, Palacios, Philip M, Nowak, Chance M, Welch, Raymond P, Li, Shaobo, Luzuriaga, Michael A, Bleris, Leonidas, Pierce, Brad S, Sherry, A. Dean, Gassensmith, Jeremiah J
• Format: Article
• Language: English
• Subjects: Animals; Chemistry, Pharmaceutical; Click Chemistry; Contrast Media - chemistry; Electron Spin Resonance Spectroscopy - methods; HeLa Cells; Humans; Magnetic Resonance Imaging - methods; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Molecular Imaging - methods; Molecular Probes - chemistry; Nanoconjugates - chemistry; RAW 264.7 Cells; Superoxides - metabolism; Tobacco Mosaic Virus - chemistry
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b00262

Superoxide overproduction is known to occur in multiple disease states requiring critical care; yet, noninvasive 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 vivo to 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 T 1 contrast at low field (