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

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

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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 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 a "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.

Original languageEnglish (US)
Pages (from-to)2973-2983
Number of pages11
JournalMolecular Pharmaceutics
Volume15
Issue number8
DOIs
StatePublished - Aug 6 2018

Keywords

  • bioconjugation
  • electron paramagnetic resonance
  • magnetic resonance imaging
  • organic radical contrast agents
  • reactive oxygen species
  • tobacco mosaic virus

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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  • Cite this

    Dharmarwardana, M., Martins, A. F., Chen, Z., Palacios, P. M., Nowak, C. M., Welch, R. P., Li, S., Luzuriaga, M. A., Bleris, L., Pierce, B. S., Sherry, A. D., & Gassensmith, J. J. (2018). Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor. Molecular Pharmaceutics, 15(8), 2973-2983. https://doi.org/10.1021/acs.molpharmaceut.8b00262