Achieving Biocompatible SABRE: An in vitro Cytotoxicity Study

Abstract

Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using in vitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion‐exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future in vivo study.

Catalyst‐Substrate Effects on Biocompatible SABRE Hyperpolarization

“…This trend is consistent with data reported for their respective polarization levels in non‐aqueous solutions and was suggested to be due to reduced spin dilution and increased relaxation times upon deuteration . Both d 22 ‐IMes and d 24 ‐IMes showed significant improvements over protio‐IMes which gave a 105‐fold signal gain …”

“…As expected, higher bolus volumes (>2.5 %) led to toxicity over short exposure times. This is consistent with our previous report using unlabeled [IrCl(COD)(IMes)] and d 2 ‐MN . As the treatment prolonged, we observe only a slight reduction in the rate of cell death when fully deuterated [IrCl(COD)( d 24 ‐IMes)] is employed (Figure B).…”

“…Conversely, the dominant factor in cell death was caused by the active SABRE catalyst, even at low concentration and exposure times. Importantly, this effect could be negated by removal of the catalyst using either catalyst deactivation and removal by ion exchange chromatography or bi‐phasic catalysis . Subsequently, catalyst capture using solid phase scavengers and subsequent filtration has proven an efficient method for catalyst depletion .…”

Iridium α‐Carboxyimine Complexes Hyperpolarized with para‐Hydrogen Exist in Nuclear Singlet States before Conversion into Iridium Carbonates

“…Hence, p ‐H 2 now reflects a truly versatile hyperpolarization platform and it is not surprising that high sensitivity analytical approaches have been demonstrated ,. The necessary progress into aqueous media has also been significant and is expected to lead to successful in vivo study in the future ,…”

Hyperpolarized NMR Spectroscopy: d‐DNP, PHIP, and SABRE Techniques

“…recently achieved 300–3000‐fold enhancements by using phase‐transfer catalysis . In this method, a homogeneous SABRE catalyst was still used in an organic solvent; however, after the hyperpolarization step, the HP substrate was partitioned away from the catalyst into an immiscible aqueous phase …”