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Molecular Imaging and Biology

09-11-2023 | Research Article

SOX71, A Biocompatible Succinyl Derivative of the Triarylmethyl Radical OX071 for In Vivo Quantitative Oxygen Mapping Using Electron Paramagnetic Resonance

Authors: Misa A. Shaw, Martin Poncelet, Navin Viswakarma, Gian Paolo Vallerini, Safa Hameed, Teresa D. Gluth, Werner J. Geldenhuys, Emily H. Hoblitzell, Timothy D. Eubank, Boris Epel, Mrignayani Kotecha, Benoit Driesschaert

Published in: Molecular Imaging and Biology

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Abstract

Purpose

This study aimed to develop a biocompatible oximetric electron paramagnetic resonance (EPR) spin probe with reduced self-relaxation, and sensitivity to oxygen for a higher signal-to-noise ratio and longer relaxation times at high oxygen concentration, compared to the reference spin probe OX071.

Procedures

SOX71 was synthesized by succinylation of the twelve alcohol groups of OX071 spin probe and characterized by EPR at X-Band (9.5 GHz) and at low field (720 MHz). The biocompatibility of SOX71 was tested in vitro and in vivo in mice. A pharmacokinetic study was performed to determine the best time frame for EPR imaging. Finally, a proof-of-concept EPR oxygen imaging was performed on a mouse model of a fibrosarcoma tumor.

Results

SOX71 was synthesized in one step from OX071. SOX71 exhibits a narrow line EPR spectrum with a peak-to-peak linewidth of 66 mG, similar to OX071. SOX71 does not bind to albumin nor show cell toxicity for the concentrations tested up to 5 mM. No toxicity was observed after systemic delivery via intraperitoneal injection in mice at twice the dose required for EPR imaging. After the injection, the probe is readily absorbed into the bloodstream, with a peak blood concentration half an hour, post-injection. Then, the probe is quickly cleared by the kidney with a half-life of ~ 45 min. SOX71 shows long relaxation times under anoxic condition (T1e = 9.5 µs and T2e = 5.1 µs; [SOX71] = 1 mM in PBS at 37 °C, pO2 = 0 mmHg, 720 MHz). Both the relaxation rates R1e and R2e show a decreased sensitivity to pO2, leading to twice longer relaxation times under room air conditions (pO2 = 159 mmHg) compared to OX071. This is ideal for oxygen imaging in samples with a wide range of pO2. Both the relaxation rates R1e and R2e show a decreased sensitivity to self-relaxation compared to OX071, with a negligible effect of the probe concentration on R1e. SOX71 was successfully applied to image oxygen in a tumor.

Conclusion

SOX71, a succinylated derivative of OX071 was synthesized, characterized, and applied for in vivo EPR tumor oxygen imaging. SOX71 is highly biocompatible, and shows decreased sensitivity to oxygen and self-relaxation. This first report suggests that SOX71 is superior to OX071 for absolute oxygen mapping under a broad range of pO2 values.
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Metadata
Title
SOX71, A Biocompatible Succinyl Derivative of the Triarylmethyl Radical OX071 for In Vivo Quantitative Oxygen Mapping Using Electron Paramagnetic Resonance
Authors
Misa A. Shaw
Martin Poncelet
Navin Viswakarma
Gian Paolo Vallerini
Safa Hameed
Teresa D. Gluth
Werner J. Geldenhuys
Emily H. Hoblitzell
Timothy D. Eubank
Boris Epel
Mrignayani Kotecha
Benoit Driesschaert
Publication date
09-11-2023
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-023-01869-8