In vivo aggregation-induced transition between T1 and T2 relaxations of magnetic ultra-small iron oxide nanoparticles in tumor microenvironment

Abstract

Surface ligands and their densities may significantly influence the optic, electric, and stable properties of inorganic nanoparticles as well as their magnetic resonance imaging (MRI) characters. In this study, ultra-small iron oxide nanoparticles with hyaluronic acid as surface ligand (Fe₃O₄@HA) were designed to target tumor cells and tune the T₁- and T₂-weighted MRI by aggregating in the tumor microenvironment via the degradation of HA upon exposure to hyaluronidase (HAase) with decreasing pH. To realize this purpose, four kinds of Fe₃O₄@HA nanoparticles with increasing HA density were synthesized and characterized. Fe₃O₄@HA₂₈₀, with higher r₁ value than others, was chosen for the signal modulation test in vitro; the T₂ signal was enhanced by 36%, and the T₁ signal decreased by 22% in the presence of HAase and acidic environment during the measurement. However, the chitosan-coated Fe₃O₄ nanoparticles did not show a similar tendency. The overlapping sections in the signal change graph of MDA-MB-231 cells and tumor-bearing mice also validate the self-assembling ability of Fe₃O₄@HA₂₈₀. Meanwhile, the tumor mapping graphs indicate the excellent tumor penetration of Fe₃O₄@HA₂₈₀, which facilitates this self-assembly process and enhances the interior section contrast of the tumor. This fundamental technique for tuning magnetic properties by the tumor microenvironment may provide a useful strategy for the rational synthesis of other inorganic nanoparticles in the field of tumor diagnostics and therapy.