A Smart Self‐Immobilization Magnetic Resonance Contrast Agent for Delayed Tumor Imaging In Vivo

Abstract Achieving tumor‐specific accumulation and high relaxivity remains critical yet challenging for improving magnetic resonance imaging (MRI) probe sensitivity. Here, we present P‐QM‐Gd , an enzyme‐responsive, self‐immobilizing small‐molecule MRI probe designed for high‐sensitivity tumor imaging. Upon activation by membrane‐bound alkaline phosphatase (ALP), P‐QM‐Gd is enzymatically converted to generate reactive quinone methide intermediates. These intermediates readily undergo nucleophilic addition with proximal protein residues, enabling the covalent conjugation of paramagnetic gadolinium complexes directly onto tumor cell membranes. This enzymatic self‐immobilization markedly increased the longitudinal relaxivity ( r 1 ) from 7.35 to 13.15 mM −1 s −1 (0.5 T, 21.3 MHz, 32 °C) and effectively “traps” the probe at the tumor site. P‐QM‐Gd showed rapid tumor uptake and efficient covalent labeling, achieving distinct MR contrast enhancement (> 60%). The imaging window was extended for up to 24 h in subcutaneous HeLa and orthotopic K7M2 tumor models. Notably, delayed MRI with P‐QM‐Gd enabled precision visualization of ∼1.3 mm orthotopic K7M2 tumors in mice. By overcoming the rapid washout and low sensitivity inherent to traditional small‐molecule MRI probes through this enzymatic self‐immobilization strategy, P‐QM‐Gd offers a promising approach for high‐sensitivity, high‐spatial resolution delayed tumor MRI, making it particularly effective for early‐stage lesion detection.