Redox-Triggered Self-Assembly of Gadolinium-Based MRI Probes for Sensing Reducing Environment

Controlled self-assembly of small molecule gadolinium (Gd) complexes into nanoparticles (GdNPs) is emerging as an effective approach to design activatable magnetic resonance imaging (MRI) probes and amplify the r₁ relaxivity. Herein, we employ a reduction-controlled macrocyclization reaction and self-assembly to develop a redox activated Gd-based MRI probe for sensing a reducing environment. Upon disulfide reduction at physiological conditions, an acyclic contrast agent 1 containing dual Gd-chelates undergoes intramolecular macrocyclization to form rigid and hydrophobic macrocycles, which subsequently self-assemble into GdNPs, resulting in a ∼60% increase in r₁ relaxivity at 0.5 T. Probe 1 has high r₁ relaxivity (up to 34.2 mM(-1) s(-1) per molecule at 0.5 T) upon activation, and also shows a high sensitivity and specificity for MR detection of thiol-containing biomolecules.