Time-resolved T₁ and T₂ contrast for enhanced accuracy in MRI tumor detection

Stimuli-responsive contrast agents (CAs) have shown great promise in enhancing magnetic resonance imaging (MRI) for more accurate tumor diagnosis. However, current CAs still face challenges in achieving high accuracy due to their low specificity and contrast signals being confounded by potential endogenous MRI artifacts. Herein, an extremely small iron oxide nanoparticle (ESIONP)-based smart responsive MRI contrast agent (LESPH) is proposed, which is meticulously designed with sequential dual biochemical stimuli-initiated, time-resolved T₁ and T₂ contrast presentation, ensuring high tumor specificity while minimizing interference from endogenous artifacts. LESPH is constructed using emulsion solvent evaporation by assembling poly(2-(hexamethyleneimino) ethyl methacrylate) terminally conjugated with a disulfide bond-linked catechol group (DSPH)-modified ESIONPs, with lauryl betaine serving as a surfactant. When LESPH undergoes sequential responses to the weak acidity and high-concentration glutathione (GSH) in the tumor microenvironment, it experiences an extremely rapid transition from sparse ESIONP assemblies to dispersed ESIONPs, followed by a slower transition to closely aggregated ones, concomitantly providing distinguishable brightening and darkening contrast enhancement at the tumor location on different time scales. By virtue of its sequential dual responsiveness and time-resolved distinguishable contrast enhancements, LESPH successfully detects tumors with extremely high accuracy, providing a novel paradigm for the precise medical diagnosis of cancer.