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

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

doi:10.1039/D0PY00558D

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

Hung V.-T. Nguyen,

‡^abcd Alexandre Detappe,

‡^bcde Peter Harvey,

^f Nolan Gallagher,^a Clelia Mathieu,^cd Michael P. Agius,^cd Oksana Zavidij,^cd Wencong Wang,^a Yivan Jiang,^a Andrzej Rajca,

^g Alan Jasanoff,^fhi Irene M. Ghobrial,^cd P. Peter Ghoroghchian*^bcd and Jeremiah A. Johnson

*^ab

Author affiliations

* Corresponding authors

^a Department of Chemistry, Massachusetts Institute of Technology (MIT), 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

^b David H. Koch Institute for Integrative Cancer Research, MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
E-mail: jaj2109@mit.edu, ppg@mit.edu

^c Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA

^d Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA

^e Centre Paul Strauss, 3 Rue de la Porte de l'Hopital, 67000 Strasbourg, France

^f Department of Biological Engineering, MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

^g Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588, USA

^h Department of Brain and Cognitive Sciences, MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

ⁱ Department of Nuclear Science and Engineering, MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

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.

Polymer Chemistry

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

Abstract

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

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