Redox-Sensitive Clustered Ultrasmall Iron Oxide Nanoparticles for Switchable T₂/T₁-Weighted Magnetic Resonance...

Development of novel activable dual-mode T₁/T₂-weighted magnetic resonance (MR) contrast agents with the same composition for dynamic precision imaging of tumors has been a challenging task. Here, we demonstrated a strategy to prepare clustered Fe₃O₄ nanoparticles (NPs) with redox-responsiveness to tumor microenvironment to achieve switchable T₂/T₁-weighted dual-mode MR imaging applications. In this study, we first synthesized ultrasmall Fe₃O₄ NPs with an average size of 3.3 nm and an r₁ relaxivity of 4.3 mM^-1 s^-1, and then cross-linked the single Fe₃O₄ NPs using cystamine dihydrochloride (Cys) to form clustered Fe₃O₄/Cys NPs. The Fe₃O₄ nanoclusters (NCs) possess desirable colloidal stability, cytocompatibility, high r₂ relaxivity (26.4 mM^-1 s^-1), and improved cellular uptake efficiency. Importantly, with the redox-responsiveness of the disulfide bond of Cys, the Fe₃O₄ NCs can be dissociated to form single particles under a reducing condition, hence displaying a switchable T₂/T₁-weighted MR imaging property that can be utilized for dynamic precision imaging of cancer cells in vitro and a subcutaneous tumor model in vivo due to the reductive intracellular environment of cancer cells and the tumor microenvironment. With the tumor reductive microenvironment-mediated switching of T₂ to T₁ MR effect and the ultrasmall size of the single particles that can pass through the kidney filter, the developed Fe₃O₄ NCs may be used as a promising switchable T₂/T₁ dual-mode MR contrast agent for precision imaging of different biosystems.