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

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

Abstract

© 2018 American Chemical Society. 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.

Citation

Nguyen, H. V., Detappe, A., Gallagher, N. M., Zhang, H., Harvey, P., Yan, C., …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

• Journal Article Type: Article
• Acceptance Date: Oct 18, 2018
• Online Publication Date: Nov 2, 2018
• Publication Date: Nov 27, 2018
• Deposit Date: Oct 23, 2019
• Publicly Available Date: Jan 16, 2020
• Journal: ACS Nano
• Print ISSN: 1936-0851
• Electronic ISSN: 1936-086X
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 11
• Pages: 11343-11354
• DOI: https://doi.org/10.1021/acsnano.8b06160
• Keywords: General Engineering; General Physics and Astronomy; General Materials Science
• Public URL: https://nottingham-repository.worktribe.com/output/2828867
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsnano.8b06160
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acsnano.8b06160