Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging

Hung V.T. Nguyen, Alexandre Detappe, Nolan M. Gallagher, Hui Zhang, Peter Harvey, Changcun Yan, Clelia Mathieu, Matthew R. Golder, Yivan Jiang, Maria Francesca Ottaviani, Alan Jasanoff, Andrzej Rajca, Irene Ghobrial, P. Peter Ghoroghchian, Jeremiah A. Johnson

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Nitroxides occupy a privileged position among plausible metal-free magnetic resonance imaging (MRI) contrast agents (CAs) due to their inherently low-toxicity profiles; nevertheless, their translational development has been hindered by a lack of appropriate contrast sensitivity. Nanostructured materials with high nitroxide densities, where each individual nitroxide within a macromolecular construct contributes to the image contrast, could address this limitation, but the synthesis of such materials remains challenging. Here, we report a modular and scalable synthetic approach to nitroxide-based brush-arm star polymer (BASP) organic radical CAs (ORCAs) with high nitroxide loadings. The optimized -30 nm diameter "BASP-ORCA3" displays outstanding T2 sensitivity with a very high molecular transverse relaxivity (r2 > 1000 mM-1 s-1). BASP-ORCA3 further exhibits excellent stability in vivo, no acute toxicity, and highly desirable pharmacokinetic and biodistribution profiles for longitudinal detection of tumors by MRI. When injected intravenously into mice bearing subcutaneous plasmacytomas, BASP-ORCA3 affords distinct in vivo visualization of tumors on translationally relevant time scales. Leveraging its high sensitivity, BASP-ORCA3 enables efficient mapping of tumor necrosis, which is an important biomarker to predict therapeutic outcomes. Moreover, BASP-ORCA3 allows for detection of millimetric tumor implants in a disseminated murine model of advanced-stage human ovarian cancer that possess genetic, histological, and vascular characteristics that are similar to those seen in patients. This work establishes BASP-ORCA3 as a promising metal-free spin contrast agent for MRI.

Original languageEnglish (US)
Pages (from-to)11343-11354
Number of pages12
JournalACS Nano
Volume12
Issue number11
DOIs
StatePublished - Nov 27 2018

Keywords

  • cancer
  • magnetic resonance imaging
  • nitroxide
  • ring-opening metathesis polymerization
  • star polymers

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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    Nguyen, H. V. T., Detappe, A., Gallagher, N. M., Zhang, H., Harvey, P., Yan, C., Mathieu, C., Golder, M. R., Jiang, Y., Ottaviani, M. F., Jasanoff, A., Rajca, A., Ghobrial, I., Ghoroghchian, P. P., & Johnson, J. A. (2018). Triply Loaded Nitroxide Brush-Arm Star Polymers Enable Metal-Free Millimetric Tumor Detection by Magnetic Resonance Imaging. ACS Nano, 12(11), 11343-11354. https://doi.org/10.1021/acsnano.8b06160