Composition-Tunable Ultrasmall Manganese Ferrite Nanoparticles: Insights into their <i>In Vivo</i> T₁ Contrast Efficacy

Abstract

The development of a highly efficient, low-toxicity, ultrasmall ferrite nanoparticle-based T₁ contrast agent for high-resolution magnetic resonance imaging (MRI) is highly desirable. However, the correlations between the chemical compositions, <i>in vitro</i> T₁ relaxivities, <i>in vivo</i> nano-bio interactions and toxicities remain unclear, which has been a challenge in optimizing the <i>in vivo</i> T₁ contrast efficacy. <b>Methods</b>: Ultrasmall (3 nm) manganese ferrite nanoparticles (Mn_xFe_3-xO₄) with different doping concentrations of the manganese ions (x = 0.32, 0.37, 0.75, 1, 1.23 and 1.57) were used as a model system to investigate the composition-dependence of the <i>in vivo</i> T₁ contrast efficacy. The efficacy of liver-specific contrast-enhanced MRI was assessed through systematic multiple factor analysis, which included the <i>in vitro</i> T₁ relaxivity, <i>in vivo</i> MRI contrast enhancement, pharmacokinetic profiles (blood half-life time, biodistribution) and biosafety evaluations (<i>in vitro</i> cytotoxicity testing, <i>in vivo</i> blood routine examination, <i>in vivo</i> blood biochemistry testing and H&E staining to examine the liver). <b>Results</b>: With increasing Mn doping, the T₁ relaxivities initially increased to their highest value of 10.35 mM^-1s^-1, which was obtained for Mn_0.75Fe_2.25O₄, and then the values decreased to 7.64 m M^-1s^-1, which was obtained for the Mn_1.57Fe_1.43O₄ nanoparticles. Nearly linear increases in the <i>in vivo</i> MRI signals (ΔSNR) and biodistributions (accumulation in the liver) of the Mn_xFe_3-xO₄ nanoparticles were observed for increasing levels of Mn doping. However, both the <i>in vitro</i> and <i>in vivo</i> biosafety evaluations suggested that Mn_xFe_3-xO₄ nanoparticles with high Mn-doping levels (x > 1) can induce significant toxicity. <b>Conclusion</b>: The systematic multiple factor assessment indicated that the Mn_xFe_3-xO₄ (x = 0.75-1) nanoparticles were the optimal T₁ contrast agents with higher <i>in vivo</i> efficacies for liver-specific MRI than those of the other compositions of the Mn_xFe_3-xO₄ nanoparticles. Our work provides insight into the optimization of ultrasmall ferrite nanoparticle-based T₁ contrast agents by tuning their compositions and promotes the translation of these ultrasmall ferrite nanoparticles for clinical use of high-performance contrast-enhanced MRI.