Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems

Nguyen, Hung V.-T.; Detappe, Alexandre; Harvey, Peter; Gallagher, Nolan; Mathieu, Clelia; Agius, Michael P.; Zavidij, Oksana; Wang, Wencong; Jiang, Yivan; Rajca, Andrzej; Jasanoff, Alan; Ghobrial, Irene M.; Ghoroghchian, P. Peter; Johnson, Jeremiah A.

Abstract

Nitroxide-based organic-radical contrast agents (ORCAs) are promising as safe next-generation magnetic resonance imaging (MRI) tools. Nevertheless, stimuli-responsive ORCAs that enable MRI monitoring of prodrug activation have not been reported; such systems could open new avenues for prodrug validation and image-guided drug delivery. Here, we introduce a novel “pro-ORCA” concept that addresses this challenge. By covalent conjugation of nitroxides and drug molecules (doxorubicin, DOX) to the same brush-arm star polymer (BASP) through chemically identical cleavable linkers, we demonstrate that pro-ORCA and prodrug activation, i.e., ORCA and DOX release, leads to significant changes in MRI contrast that correlate with cytotoxicity. This approach is shown to be general for a range of commonly used linker cleavage mechanisms (e.g., photolysis and hydrolysis) and release rates. Pro-ORCAs could find applications as research tools or clinically viable “reporter theranostics” for in vitro and in vivo MRI-correlated prodrug activation.

Citation

Nguyen, H. V.-T., Detappe, A., Harvey, P., Gallagher, N., Mathieu, C., Agius, M. P., …Johnson, J. A. (2020). Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems. Polymer Chemistry, 11(29), 4768-4779. https://doi.org/10.1039/d0py00558d

• Journal Article Type: Article
• Acceptance Date: Jun 22, 2020
• Online Publication Date: Jun 26, 2020
• Publication Date: Aug 7, 2020
• Deposit Date: Aug 5, 2020
• Publicly Available Date: Aug 6, 2020
• Journal: Polymer Chemistry
• Print ISSN: 1759-9954
• Electronic ISSN: 1759-9962
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Issue: 29
• Pages: 4768-4779
• DOI: https://doi.org/10.1039/d0py00558d
• Keywords: Organic Chemistry; Biochemistry; Bioengineering; Polymers and Plastics
• Public URL: https://nottingham-repository.worktribe.com/output/4759747
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2020/py/d0py00558d#!divAbstract
• Additional Information: : This document is Similarity Check deposited; : Supplementary Information; : Hung V.-T. Nguyen (ORCID); : Alexandre Detappe (ORCID); : Peter Harvey (ORCID); : Peter Harvey (ResearcherID); : Andrzej Rajca (ORCID); : Jeremiah A. Johnson (ORCID); : Jeremiah A. Johnson (ResearcherID); : Single-blind; : Received 17 April 2020; Accepted 22 June 2020; Accepted Manuscript published 26 June 2020; Advance Article published 8 July 2020