Reduced Magnetic Coupling in Ultrasmall Iron Oxide T₁ MRI Contrast Agents

Contrast agents for magnetic resonance imaging (MRI) are essential for evidential visualization of soft tissues pathologies. Contrast-enhanced MRI can be carried out with T₁- and T₂-weighted sequences that require as contrast agents paramagnetic and superparamagnetic materials, respectively. The T₁-weighted imaging is frequently preferred over T₂-, as it induces a bright contrast for sharper image analysis and allows more rapid image acquisition. Commonly used and FDA-approved T₁ contrast agents, however, were shown to be associated with nephrogenic systematic fibrosis due to Gd³⁺ release from the injected complexes. Here, ultrasmall iron oxide nanocrystals are produced by scalable flame aerosol technology and investigated as T₁ MRI contrast agents by focusing on structure-function relationships and cytocompatibility. The optimized nanocrystals are shown to be a promising cytocompatible alternative to commercial Gd-complexes as they attain comparable relaxivities with no apparent cytotoxicity at clinically relevant concentrations tested in vitro against four different cell types (PC3, HepG2, THP-1, and red blood cells). By using SiO₂ as a spacing material, the contrast enhancement could be finely tuned by decreasing the effective magnetic size of iron oxide resulting in significant T₁ contrast enhancement due to reduced magnetic coupling.