Dynamically Reversible Iron Oxide Nanoparticle Assemblies for Targeted Amplification of T1-Weighted Magnetic Resonance Imaging of Tumors

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.