Composition Tunable Ultrasmall Manganese Ferrite Nanoparticles: Insight Into Their T₁ MRI Contrast Ability

Successful development of ultra-sensitive molecular imaging nanoprobes for the detection of targeted biological objects is a challenging task.Although magnetic nanoprobes have the potential to perform such a role,the results from probes that currently available have been far from optimal.Therefore,the development of new types of nanoparticles is particularly important.In this regard,a metal dopant substitution strategy of metal ferrite nanoparticles has been pursued to achieve high and tunable nanomagnetism.The manganese ferrite nanoparticle represents an important class of magnetic nanoparticles,mostly as highly sensitive magnetic resonance imaging（MRI）nanoprobes have been well developed in recent years.However the understanding the correlations between metal doping and in vitro MR relaxivity and in vivo MRI contrast ability is still not thoroughly understood.Herein,we systematically evaluate the effects of manganese doping on change of ultrasmall ferrite（3 nm）T₁ contrast abilities in vitro and in vivo.（1）We used a general dynamic simultaneous thermal decomposition（DSTD）strategy for controllable synthesis of monodisperse ultrasmall manganese ferrite nanoparticles(Mn_xFe_3-xO₄)with different manganese levels（x=0.32-1.57）.The Mn²⁺doping level,a key parameter,was carefully controlled by varying the initial molar ratio of the iron-eruciate and manganese-oleate.TEM images demonstrate that the ultrasmall manganese ferrite nanoparticles were fairly uniform in size with a narrow distribution and high crystallinity.The powder X-ray diffraction（XRD）patterns of as-prepared nanoparticles were in good accord with the standard spinel MnFe₂O₄ powder diffraction data,and no other secondary phases such as manganese oxide or ferrous oxide could be traced.The saturation magnetization and ferrite nanoparticles increase along with rising manganese proportion,peak when the doping level of Mn_xFe_3-xO₄ reaches x=0.75,and decrease dramatically as the manganese percentage continues to augment.（2）Phosphorylated mPEG is used for surface modification by ligand exchange.The obtained hydrophilic ultrasmall manganese ferrite nanoparticles show very good uniformity and unchanged particle size.Preliminary studies have shown that the PEG1000and PEG2000 modified nanoparticles exhibited excellent colloidal stability in deionized（DI）water after a 10-day incubation at room temperature,as there was no apparent change in size and polydispersity index（PDI）.However,the hydrodynamic size of the PEG5000modified nanoparticles was observed to be stable for only 2 days.（3）We evaluated the potential of using various manganese nanoparticles in MR imaging applications.By systematically elucidating the magnetic characteristics and the MR signal enhancement effect,which we discovered the synthesized Mn_xFe_3-xO₄nanoparticles（x=0.76）exhibited the highest r₁ relaxivity(up to 10.36 mM^-1s^-1)at 3.0 T among all the manganese ferrite nanoparticles.Finally,we tested its applicability as a molecular imaging probe for liver imaging.T₁ contrast ability of manganese ferrite nanoparticles increase along with rising manganese proportion.Our study offers possibilities for the chemical design of a highly sensitive ultrasmall magnetic nanoparticle based T₁ MRI probe for various clinical diagnosis applications.