| Clinical diagnosis has great demand for contrast-enhanced magnetic resonance imaging(MRI).However,the traditional superparamagnetic iron oxide nanoparticles(SPIO)-based T2 contrast agent may induce clinical misdiagnosis due to the intrinsic dark signal in T2-weighted MRI.The nephrogenic systemic fibrosis and the gadolinium retention in the central nervous system are observed in the patients who receive the gadolinium-based T1 contrast agent enhanced MRI.These intrinsic limits of the SPIO-and Gd-based contrast agents prompted the development and application of ultra-small iron oxide nanoparticles based T1 contrast agent for more effective and safer detection and diagnosis.Considerable progress has been achieved in this field,but the main challenge to ultra-sensitive imaging nanoprobes for the detection of targeted biological objects becoming a new paradigm in nanomedicine stem from the absence of general strategy for synthesis of monodispersed ultra-small ferrite nanoparticles,an incomplete understanding of correlations between chemical composition and MR signal enhancement and the insignificant contrast between tumor tissue and normal tissue.These problems seriously restrict the clinical translation of nanodiagnostics.Having broken the limitations of the hydrolytic non-diffusion limited method and the different decomposition dynamics of mixed metal precursors in co-thermal decomposition,we developed a general dynamic simultaneous thermal decomposition(DSTD)strategy for controllable synthesis of monodisperse ultra-small metal ferrite nanoparticles with sizes smaller than 4 nm.Using ultra-small Mn Fe2O4 nanoparticles(UMFNPs)as a model system,the as-prepared UMFNPs show the extremely small size,narrow size distribution,stoichiometric composition and high crystallinity.The comparison study revealed that the DSTD using the iron-eruciate paired with a metal-oleate precursor enabled a nucleationdoping process,which is crucial for particle size and distribution control of ultrasmall metal ferrite nanoparticles.The principle of DSTD synthesis has been further confirmed by synthesizing Ni Fe2O4 and Co Fe2O4 nanoparticles with well-controlled sizes of ?3 nm.The magnetic characterizations show the UMFNPs are superparamagnetic behavior at room temperature with saturation magnetization(Ms)for 2,3,and 3.9 nm sized particles are 18.59,24.91,and 29.18 emu g-1.The phosphorylated m PEG is used for surface modification of UMFNPs by ligand exchange.Preliminary studies have shown that the UMFNPs exhibited excellent colloidal stability in DI water,normal saline,different concentrations of NaCl solution,and cell culture medium containing 10% FBS after a 12-day incubation at room temperature.These results show the ultra-small ferrite nanoparticles are successfully synthesized.Taking UMFNPs as a model system,the synthesized UMFNPs exhibited the highest r1 relaxivity(up to 8.43 m M-1 s-1)among the ferrite nanoparticles with similar sizes reported so far and two times folder than that of clinical Omniscan contrast agent.The UMFNPs can be used as a multifunctional T1 MR nanoprobe for in vivo high-resolution blood pool and liver-specific MRI simultaneously.The UMFNPs enhanced MRI shows the resolution of the image is very high,such that even the 0.47 mm veins can be accurately imaged.The pharmacokinetics results show that the blood half-life(t1/2)of the UMFNPs is about 0.31 h.the UMFNPs is excreted from the body via the renal clearance pathway and the hepatobiliary pathway are 30.33% and 67.40% respectively within 60 h.The biosafety results show that there were no obvious pathological changes in organs,indicating the safe use of the UMFNPs for potential clinical trials.To enhance the contrast between the tumor tissue and the normal tissue,we developed the Glu-Ure-Lys peptide-conjugated UMFNPs(UMFNP-Glu),which can be used as an activetargeted contrast agent for detention of prostate tumor.UMFNP-Glu samples show insignificant toxicity with a cell viability of more than 80% at [Fe+Mn] concentration of less than 100 ?g/m L,indicating the UMFNP-Glu is safe for the LNCa P prostate epithelial cells and PC3 prostate epithelial cells.The confocal laser-scanning microscope images show the fluorescence signals were most evident in the cytoplasm of LNCa P cells treated with UMFNP-Glu,whereas little or no fluorescence was observed in PC3 cells treated with the same nanoparticles.These results clearly show that high targeting efficacy of UMFNP-Glu to the LNCa P cells.The in vivo T1 MRI of a LNCa P xenograft mouse show the increase in MR T1 signal was 19.8% compared to pre-injection,indicating a large accumulation of the UMFNP-Glu within the tumor.The as prepared UMFNP-Glu contrast agent contribute for ultra-sensitive imaging tumor.Liver is a highly frequent site of tumors,including primary liver cancers and metastases.Therefore,there remains a pressing demand to develop liver-specific contrast agent to realized the contrast enhanced MRI for detection of liver tumor.The heterogeneity of tumor biology and the off-target effects result in the low contrast between normal tissue and tumor.We developed a liver-specific contrast agent with significant and contrast between liver parenchyma and liver tumor.This liver-specific contrast agent consists of the 3 nm UMFNP and ethoxybenzyl group(UMFNP-EOB).The toxicology investigation shows the UMFNPEOB with insignificant toxic effect,which can ensure the biosafety in the in vivo MRI.The evaluation of the detection efficiency of the liver-specific contrast agent UMFNP-EOB were carried out in the rabbits' liver VX2 tumor model.The UMFNP-EOB are preferentially accumulated in the liver parenchyma,resulting in the enhancement of liver parenchyma in the T1 MRI.The liver VX2 tumors with poor vascularization show the hypointensity.The contrast-to-noise ratio(CNR)between the liver parenchyma and the tumor is as high as 84.1%.The UMFNP-EOB contrast agent can overcome the problem of heterogeneity of tumor biology and the off-target effects resulting in the low contrast between normal tissue and tumor,and providing a new direction for developing ultra-sensitive contrast agent.This article solved the scientific problems which can be the obstacle for the development of iron oxide nanoparticles-based MRI contrast agent.We developed a general DSTD strategy for synthesis of ultra-small metal ferrite nanoparticles.Using UMFNPs as a model system,clearly defined correlations between chemical composition and MR T1 signal enhancement,and developed UMFNPs-based ultra-seneitive T1 contrast agent.This work provides a theoretical and applied foundation for the development of ultra-samll ferrite nanoparticlesbased MRI contrast agent,which contribute to ultra-small ferrite nanoparticles-based contrast agent for clinical translation. |
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