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

Development of novel activable dual-mode T-1/T-2-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 T-2/T-1-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 r, 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 r(2) 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 T-2/T-1-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 T-2 to T-1 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 T-2/T-1 dual-mode MR contrast agent for precision imaging of different biosystems.