An activatable Mn(II) MRI probe for detecting peroxidase activity in vitro and in vivo

Abstract

Myeloperoxidase (MPO), a hallmark of the function and activation of innate immune cells, can act as a ‘double-edged sword’, contributing to clear infection as well as causing tissue oxidizing damage in various inflammatory diseases. In this study, an activatable Mn(II) chelate-based magnetic resonance imaging (MRI) contrast agent (CA), Mn-TyEDTA (TyEDTA = tyrosine derived ethylenediaminetetraacetic acid) structurally featuring a phenol group as the electron-donor, was developed to sense the activity of peroxidase in vitro and in vivo. Mn-TyEDTA demonstrated a peroxidase activity-dependent relaxivity in the presence of horseradish peroxidase (HRP)/H2O2 with more than a 2.6-fold increase in water proton relaxivity produced (HRP, 500 U; H2O2, 4.5 eq). A mechanism of peroxidase-mediated Mn(II) monomer radical polymerization was confirmed with those oligomers of Mn-TyEDTA such as dimer, trimer and tetramer were found in the LC-MS study. Dynamic MR imaging of normal mice revealed rapid blood clearance and mixed renal and hepatobiliary elimination of Mn-TyEDTA. Furthermore, compared to liver-specific and non-specific extracellular contrast agents (Mn-BnO-TyEDTA (BnO-TyEDTA = benzyl tyrosine-derived ethylenediaminetetraacetic acid) and Gd-DTPA (DTPA = diethylene triamine penta-acetic acid)), MRI on a monosodium urate (MSU) crystal-induced acute mice model of arthritis showed that inflamed tissues could be selectively enhanced by Mn-TyEDTA, suggesting that this peroxidase-activatable Mn(II) MRI probe could potentially be used for noninvasive detection of MPO activity in vivo.