Extremely Small Iron Oxide Nanoparticle-Encapsulated Nanogels as a Glutathione-Responsive T₁ Contrast Agent for Tumor-Targeted Magnetic Resonance Imaging

Activatable magnetic resonance imaging (MRI) contrast agents that can be selectively stimulated at a tumor region are urgently demanded to realize the efficient and accurate diagnosis of cancers. Here, extremely small iron oxide nanoparticles (ESIONPs) modified with citric acid (ESIONPs-CA) are encapsulated in disulfide-cross-linked poly(carboxybetaine methacrylate) (poly(CBMA)) nanogels, and a cyclo[Arg-Gly-Asp-d-Tyr-Lys] (c(RGD)) ligand is further introduced to obtain ESIONP-packaged poly(CBMA) nanogels equipped with tumor-targeted c(RGD) (ICNs-RGD). On the basis of the transformation of the clustered ESIONPs into dispersed ones induced by the reducing glutathione (GSH), ICNs-RGD can complete the conversion from a T2 contrast agent to a T1 one, realizing the selective activation of the T1 contrasting effect. The GSH-dependent MRI signal conversion of ICNs-RGD is feasible in the tumor cell and tissue. Moreover, ICNs-RGD exhibits obvious targeting specificity and favorable biocompatibility. In the MRI experiments of tumor-bearing mice, benefiting from the stimuli-responsiveness toward GSH and targeting specificity, the T1 contrasting effect of tumor tissues can be selectively enhanced after the intravenous injection of ICNs-RGD. Therefore, tumor-targeted ICNs-RGD with a switchable MRI signal derived from the activation of GSH is a potential contrast agent for the efficient and precise tumor diagnosis in the clinic.