| Magnetic iron oxide nanoparticles?MIONs?have been widely studied and applied in biomedical fields,such as magnetic resonance imaging?MRI?,drug delivery,magnetic hyperthermia,immunoassay,and bio-molecular extraction,due to unique physicochemical characteristics.These materials build new opportunities and platforms for the development of biomedicine.In the field of biomedical medicine,the ideal magnetic nanoparticles should follow the criteria of clear structure,stable physicochemical properties,highly dispersed,stable dispersion,large-scale production,good biocompatibility,and effective applications in vivo.Currently,the main synthesis routes of magnetic iron oxide nanoparticles are chemical co-precipitation and thermal decomposition.The greatest advantage of chemical co-precipitation method lies in the massive production,and it is the only process that can meet the demand of medical and industrial production at present.However,poor repeatability among batches and the difficulty in controlling the physical and chemical properties of the products are the obvious shortcomings.Thermal decomposition route has excellent product quality control,that is,the particle size of the product is highly mono-disperse.Unfortunately,the deadliest problem with the method is that the product is hydrophobic,which means that they cannot be directly used in the biomedicine.Therefore,hydrophilic surface modification is necessary,at a cost of the complex and costly surface engineering is complex and costly.As a result,the expense of using such water-soluble MIONs?WMIONs?is high,which then results in severely restricts of the wider market applications.In view of challenges,three topics are mainly covered in this study.The first is to develop a new preparation route to synthesize WMIONs.The nanoparticles are endowed with features of high saturation magnetization,highly dispersed and stable dispersion in water without any surface engineering.Secondly,the formation mechanism of WMIONs based on the new process is studied,and the structure of the product is also further confirmed.In the third research project,aqueous dispersions of WMIONs are used as contrast agents for MRI.Results show that the contrast agents have high lateral relaxation efficiency?r2?and longitudinal relaxation efficiency?r1?,and prominent contrast imaging effects in vivo.1.Deep eutectic solvent-electrolysis is proposed and developed to synthesize WMIONs.The deep eutectic solvent?DES?-electrolysis is first proposed and developed for the preparation of WMIONs.For the preparation of the magnetic nanoparticles,the high purity iron plate is used as cathode and anode,respectively.DESs composed of urea and choline organic matters are employed as electrolytes.When the electrolysis begins,the iron?Fe0?at the interface between DES and anode electrode is finally oxidized to be ferric irons(Fe3+),and then they are combined with the reactive oxygen species?O·?which are also generated near the anode to form iron oxide nanocrystals.Concomitantly,hydrophilic groups produced by electrolyte decomposition such as amino?-NH2?will be grafted on or combined with the nanoparticles.The obtained WMIONs are identified as mono-disperse maghemite??-Fe2O3?.The as-obtained WMIONs have high saturation magnetization,excellent hydrophilicity,high water dispersibility,and stable dispersion stability.WMIONs can be synthesized for more than 600 grams at the laboratory setup in a batch.The nanoparticles are preliminary identified as ferrimagnetic.The saturated magnetization value is greater than 65.0 emu g-1,the coercivity is not higher than 35 Oe,and the remanence is below 7.5%.The TEM size of nanoparticles is 7-9 nm.The hydrodynamic diameter is 20-30 nm,and the polydispersity indexes are less than 0.03.The Zeta potential is higher than+40 mV,and the aqueous dispersion can be stably maintained for more than 600 without coagulation or stratification.2.Research on the formation mechanism of?-Fe2O3.In order to further confirm the product structure,that is whether there are other kinds of iron oxide generated except for?-Fe2O3.High purity iron plates are employed as cathode and anode,respectively.The electrolytes are not only consisted of DES,but also contain ferrous ion(Fe2+).The electrolysis process is similar to the preparation of WMIONs which has been described above.Results show that even with sufficient Fe2+in the electrolyte,the product is still?-Fe2O3 rather than Fe3O4 and other iron oxides or hydroxides.3.Applications of WMIONs on the MRI.Before the water-soluble ferrimagnetic?-Fe2O3nanoparticles are used as candidates for iron oxide-based contrast agents?IOCAs?,cellular uptake and biocompatibility should be examined.The composite that FITC labeled on?-Fe2O3nanoparticles is confirmed by the UV-visible spectroscopy.The cellular uptake of nanoparticles is observed by the confocal laser scanning microscopy.HepG2 cells are employed to evaluate the cytotoxicity of the?-Fe2O3 nanoparticles by MTT colorimetric assays.Results of cellular cytotoxicity assays,either based on the time dependent or the concentration gradient evaluations,indicate that the WMIONs have no significant cytotoxicity.The r1 and r2 relaxivities of the WIONs are measured.Values of r2 and r1 are 497.8 mM s-1and 179.7 mM s-1,respectively,and then the ratio of r2/r1 is calculated as 2.77.It means that the WIONs have great potential to be used as IOCAs for MRI,and it can even be used as a dual-mode contrast agent?T1-T2?.Results showed the magnetic nanoparticles are more suitable to be used as T2-weighted and T1-weighted IOCAs at higher doses and lower doses,respectively.The WIONs have no effective MRI targeting for liver tumors.In summary,a DES-based electrolysis processes is proposed and implemented to synthesize WIONs.Physicochemical characteristics of WIONs in batches are stable and highly repeatable.Products have features of clear structure,mono-disperse particle size distribution,high saturation magnetization,highly dispersible and stable dispersion without surface modification,good biocompatibility,and high r1 and r2 relaxivity values.It fulfills the basic physicochemical properties of magnetic nanoparticles applied in vivo MRI,and lays a foundation for the development of a next-generation of commercial single-mode?T1 or T2?or dual-modal?T1-T2?IOCAs. |
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