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

• Published in: Polymer Chemistry
• Main Authors: 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.
• Format: Text
• Language: English
• Published: 2020
• Subjects: Article; Orca
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009311/; http://www.ncbi.nlm.nih.gov/pubmed/33790990; https://doi.org/10.1039/d0py00558d

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.