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

preprint
submitted on 09.05.2018 and posted on 10.05.2018 by Madushani Dharmarwardana, André F. Martins, Zhuo Chen, Philip M. Palacios, Chance M. Nowak, Raymond P. Welch, Shaobo Li, Michael A. Luzuriaga, Leonidas Bleris, Brad S. Pierce, A. Dean Sherry, Jeremiah J. Gassensmith
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 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 T1 contrast at low field (<3.0 T), and T2 contrast at high field (9.4 T). Additionally, we demonstrated that the unique topology of TMV allows for “quenchless fluorescent” bimodal probe for concurrent fluorescence and MRI/EPR imaging, which was made possible by exploiting the unique inner and outer surface of the TMV nanoparticle. Finally, we show TMV-ORCAs do not respond to normal cellular respiration, minimizing the likelihood for background, yet still respond to enzymatically produced superoxide in complicated biological fluids like serum.

Funding

DMR-1654405, RP170752, AT-584, CHE, 1709369, GM117511-01-01

History

Email Address of Submitting Author

gassensmith@utdallas.edu

Email Address(es) for Other Author(s)

afm140130@utdallas.edu dean.sherry@utsouthwestern.edu bspierce@uta.edu bleris@utdallas.edu mal161930@utdallas.edu Shaobo.Li@utdallas.edu RaymondP.Welch@utdallas.edu Chance.Nowak@utdallas.edu Philip.Palacios@mavs.uta.edu Zhuo.Chen1@utdallas.edu

Institution

University of Texas at Dallas

Country

USA

ORCID For Submitting Author

0000-0001-6400-8106

Declaration of Conflict of Interest

The authors declare no competing financial interest.

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