Activatable T1/T2 dual-mode MR imaging nanoplatform for enhancing accuracy by Fe/Mn oxide heteronanocrystals

Introduction T1/T2 dual-mode contrast agents (DMCA) for magnetic resonance (MR) imaging have gained much interest for their ability to provide two complementary and reliable data within single instrument. However, most of the... [ view full abstract ]

Introduction
T1/T2 dual-mode contrast agents (DMCA) for magnetic resonance (MR) imaging have gained much interest for their ability to provide two complementary and reliable data within single instrument. However, most of the contrast agents are “always ON” systems exerting the MR contrast effect regardless of the interaction with biological targets; this can result in poor target-to-background ratios. Herein, we developed a redox-responsive activatable imaging nanosystem based on the Fe/Mn oxide core/shell heteronanocrystals functioning magnetic relaxation switch (MGRS) for T1/T2 dual-mode MR imaging. Mn3O4 shells were introduced to the nanoplatform to minimize the water proton interaction with the nanoprobe in normal condition before both immediate dissolution generating high-spin Mn2+ ions and MGRS activation under intracellular reducing environment. We investigated the OFF/ON operation mechanism of MGRS according to glutathione (GSH) levels on in vitro test, and confirmed the feasibility of the nanoprobes for in vivo T1/T2 MR imaging of tumor-bearing mice.

Methods
We synthesized Fe3O4@Mn3O4 core-shell heteronanocrystals through seed-mediated growth. As-prepared nanocrystals were encapsulated with PEG derivatives for the water-dispersibility and biocompatibility. MKN-45 gastric cancer cell line was used to evaluate feasibility of the nanoprobes for effective and activatable MR imaging performance. A xenograft tumor model was used to investigate in vivo tumor imaging with the nanoprobes.

Results and discussion
Fe3O4 and Mn3O4 were designed to be directly contacted as a core/shell heteronanocrystal structure to obtain efficient magnetic coupling between T2 and T1 materials. A popcorn-like shape and size (13.3 nm) after growth of Mn3O4 shells on the Fe3O4 nanospheres were confirmed in TEM and DLS results. Fe3O4@Mn3O4 nanoparticles were coated with polysorbate 80 to be dispersible in aqueous solution. We confirmed the redox-responsive ability of the nanoprobes by measuring its physicochemical changes (surface atomic composition, UV-vis absorbance, and MR contrast effects) after dispersion in the GSH solutions or cellular uptake. The nanoprobes showed highly enhanced T1/T2 relaxivities due to increased proton interactions and magnetic decoupling after dissolution of the Mn3O4 shells by redox reaction. We demonstrated potential utility of the nanoprobes as MR imaging agents in the animal studies showing clear T1/T2 contrast effects in the MR images.