A GGT-Activatable Chiral Gadolinium Polymer Probe for Dual-Modal MR/NIRF Imaging of Glioma

Magnetic resonance imaging (MRI) offers noninvasive, radiation-free anatomical imaging but is inherently constrained by poor sensitivity for molecular event detection. To address this, we present PAA-Gd-γ-GT, an enzyme-activatable dual-modal probe that synergizes MRI's anatomical precision with the exceptional sensitivity of near-infrared fluorescence (NIRF). The probe integrates a chiral Gd-DOTA complex featuring optimized water-exchange kinetics, a poly(acrylic acid) (PAA) scaffold for relaxivity enhancement, and a γ-glutamyl-caged NIRF fluorophore for tumor-selective activation. The probe exhibits a remarkable baseline relaxivity (r₁) of 16.1 mM^-1 s^-1, which further increases to 21.3 mM^-1 s^-1 upon GGT-mediated cleavage and subsequent albumin binding, a nearly sevenfold enhancement over clinically used Gd-DOTA (3.0 mM^-1 s^-1). Notably, postactivation intermediates enable prolonged retention within orthotopic gliomas via interaction with local biomolecules, ensuring sustained contrast without compromising biocompatibility. This design affords concurrent tumor delineation via T₁-weighted MRI and molecular validation via NIRF, establishing a robust, enzyme-responsive multimodal platform with translational potential for glioma margin identification and image-guided surgery.