Continuous preparation of a nontoxic magnetic fluid as a dual-mode contrast agent for MRI

Ultrasmall nanoparticle contrast agents provide dual-mode MRI. However, the application of ultrasmall nanoparticle contrast agents is limited by low manufacturing outputs and cumbersome preparation processes. Herein, we report a novel continuous-flow coprecipitation method for the preparation of the Fe₃O₄ nanoparticles magnetic fluid (CFCPFe) coated with ultrasmall cysteine-terminated polymethacrylic acid (Cys-PMAA). The preparation process is more coherent, simpler, and less expensive. Compared with magnetic fluids prepared by the conventional method (Cys-PMAA@Fe₃O₄), CFCPFe has smaller particle sizes (3.27 ± 0.93 nm). Moreover, CFCPFe demonstrates excellent stability for >180 days with different pH values (pH = 2-12) and salt concentrations (up to 2 mol/L). In addition, HEK293T cytotoxicity tests, hemolysis tests, and H&E tissue sections show excellent in vitro and in vivo biocompatibility. In vitro magnetic resonance imaging (MRI) at 1.5 T shows that the r₂ value (50.51 mM^-1·s^-1) of CFCPFe is slightly lower than that of Combidex (r₂ = 65 mM^-1·s^-1) and that the r₁ value (9.54 mM^-1·s^-1) is 2.7 times higher than that of Gd-DTPA (r₁ = 3.5 mM^-1·s^-1). Finally, in vivo imaging shows that CFCPFe reaches the tumor region of the mouse liver cancer model, and a small tumor can be observed in dual-mode imaging. This work offers an effective method for the preparation of a low-cost, stable, and biocompatible ultrasmall contrast agent exhibiting a strong magnetic-imaging effect for dual-mode imaging.