Development Of Quasi-paramagnetic Ultrasmall Ferrite Contrast Agents And The Application In Magnetic Resonance T1-Enhanced Imaging

Benefiting from their unique magnetic properties and good biosafety,ferrite nanomaterials including iron oxide nanoparticles are widely used in MRI clinical diagnostics and imaging studies.Recent studies have shown that ultrasmall ferrite materials with size less than 5 nm exhibit good T₁ relaxation efficacy and low r₂/r₁ ratio and can be used as T₁ contrast agents.However,their magnetic structures and relaxation enhancement mechanisms remain to be elucidated.In this study,we propose a new core/shell quasi-paramagnetic structure and investigate the structure-relaxivity relationship of ultrasmall ferrite nanoparticles;Synthesized different quasi-paramagnetic ferrite contrast agents and apply them to breast cancer MRI detection and liver specific imaging.(1)Dopants controlled synthesis of quasi-paramagnetic ferrite nanoparticles:Ultrasmall zinc ferrite nanoparticles(Zn_xFe_3-xO₄,denoted as Zn_xF)were synthesized using the dynamic simultaneous thermal decomposition(DSTD)method.The zinc doping level(x=0.1-0.9)was regulated by modulating the ratios of two metal precursors,iron eruciate complex and zinc hydroxide carbonate,which allowed the modulation of the magnetic crystalline core components of quasi-paramagnetic ferrite nanoparticles.The Mn-substituted level is adjusted by varying the Mn²⁺precursor concentration in the cation exchange reaction.The TEM,XRD,EDS mapping,and EXAFS results showed that zinc and iron elements were uniformly distributed in the ferrite nanoparticles,while manganese elements were mainly distributed on the surface of the nanoparticles,which demonstrated the feasibility of the proposed synthesis strategy.(2)Composition modulation of quasi-paramagnetic ferrite nanoparticles in vitro MRI contrast performance:The effects of the core-shell composition of ferrite nanoparticles on their relaxation properties was investigated.It is found that zinc doping can regulate the magnetization of ultrasmall ferrite nanoparticles,which in turn regulates the contribution of outer sphere relaxation and consequently the relaxivity.The substitution of manganese ions on the surface can accelerate the exchange rate between ferrite nanoparticles and surrounding water molecules,which regulates the relaxivity by affecting the contribution of inner sphere relaxation.Finally,the effect of simultaneous modulation of the core-shell composition on the relaxivity of quasi-paramagnetic ferrite nanoparticles was systematically investigated.At a zinc doping level of 0.4 and a surface manganese substitution level of 0.2(denoted as Zn_0.4F@Zn_0.4Mn_0.2F),the r₁ relaxivity of the ferrite nanoparticles reached 20.22 mM^-1s^-1,which was 5.2 times higher than that of the original ultrasmall iron oxide nanoparticles and 6.5 times higher than that of the clinically used gadolinium-based contrast agent.The unique core-shell structure of ferrite nanoparticles allows us to chemically modulate the core-shell component and adjust the contributions of both the inner and outer sphere relaxation to maximize their relaxation performance.(3)Different quasi-paramagnetic ferrite contrast agents were developed to achieve in vivo detection of breast cancer as well as liver-specific magnetic resonance imaging:To identify the 4T1 cancer cells precisely,a clinically approved CXCR4 antagonist with ultra-high affinity,AMD3100,was conjugated with Zn_0.4F@Zn_0.4Mn_0.2F nanoparticles(denoted as Zn_0.4F@Zn_0.4Mn_0.2F-AMD).Biosafety assessment suggests that Zn_0.4F@Zn_0.4Mn_0.2F-AMD is a highly biocompatible and sensitive nanoprobe.The highest tumor CNR after intravenous injection of Zn_0.4F@Zn_0.4Mn_0.2F-AMD is 33.19,which is 4.5times higher than that of?-Fe₂O₃-AMD(7.35).In vivo results reveal that the high-performing Zn_0.4F@Zn_0.4Mn_0.2F-AMD nanoprobe enables an ultrasensitive MRI tracking of the progression of small lung metastatic deposits,which will be valuable in the development of future clinical imaging diagnostics.Development of ultra-sensitive quasi-paramagnetic ferrite-based magnetic resonance imaging(MRI)T₁ contrast agent is highly desirable,but the correlations between chemical composition and in vitro T₁ relaxivity,pharmacokinetics profiles,toxicity issues remain unclear.Here we used ultra-small manganese ferrites(Mn_xFe_3-xO₄)nanoparticles with the same surface chemistry but different manganese doping levels(x=0.32,0.37,0.75,1,1.23,and 1.57)as a model system to optimize the in vivo T₁ contrast ability,through a process that involved the systematic evaluation of the in vitro T₁ relaxivity,blood half-life time,biodistribution and biosafty of the Mn_xFe_3-xO₄ nanoparticles.As the Mn doping level is increasing,the T₁ relaxivity values are increasing to the highest value of 10.36 mM^-1s^-1 for the Mn_0.75Fe_2.25O₄,nanoparticles and then decrease.The in vivo MRI and biodistribution results show the accumulation of Mn_xFe_3-xO₄ nanoparticles in the liver is increasing with the increase Mn doping level.The cytotoxicity and the blood biochemistry test results indicate that the Mn_xFe_3-xO₄ nanoparticles with the low Mn doping level(x=0.32,0.37,0.75,and 1)can induce insignificant toxicity.These systematic evaluations show the Mn_0.75Fe_2.25O₄ and Mn Fe₂O₄ nanoparticles exhibit the maximized in vivo T₁ contrast ability among the Mn_xFe_3-xO₄ nanoparticles.Our work opens an insight for optimizing high-performance T₁ contrast agents by modulating the composition of nanoparticles and promotes the in vivo use of the ultra-small ferrite nanoparticles-based MR contrast agent for various ultra-sensitive molecule imaging in nanomedicine.