Magnetic Hyperthermia Effects Of Iron Oxide Nanomaterials On Differentiation Of Macrophages And Treatment Of Breast Cancer

Macrophages are important members of the innate immune system.It plays a key role in maintaining homeostasis,immune function and pathological progression such as cancer,atherosclerosis as well as tissue regeneration.Macrophages could be polarized into different phenotypes to achieve their unique functions,including: pro-inflammatory M1 phenotype and alternatively activated M2 phenotype.These two phenotypes have different biological functions.M1 macrophages promote inflammation,kill tumors,and mediate ROS-induced tissue damage;M2 macrophages eliminate inflammation,promote tumor development,and suppress the immune.They play different roles in different diseases.It is a challenge task that how to real time remotely control of macrophages polarization.Magnetic hyperthermia has been applied on tumor treatment,and has revealed certain conclusion on its killing mechanism.But there are still new mechanisms that are being discovered to complement them.Recent studies have found that iron oxide nanomaterials that mediate magnetic hyperthermia to alter the phenotype of tumor-associated macrophages(TAMs)in the tumor microenvironment.It has been reported that the iron oxide nanomaterials mediate the mechanical effects of external magnetic fields to regulate the differentiation of cells.These findings have raised our concern about the heat induced effect of magnetic nanomaterials on macrophages.The research content of this paper is divided into the following parts:(1)7 nm and 16 nm superparamagnetic iron oxide nanoparticles with uniform size and spherical shape were prepared by high temperature organic thermal decomposition method.Vibrating sample magnetometer(VSM)according to X-ray diffraction(XRD)were carried to characterize the nanoparticles.These results show that both two particles are ferroferric oxide and superparamagnetic properties.The particle hydrodynamic diameter was measured by dynamic light scattering(DLS).The results indicate that the two particles are well dispersed.A 70 nm vortex magnetic iron oxide nanoring with uniform size and ring shape was prepared by hydrothermal method.According to XRD and DLS characterization data,the prepared nanoring component is ferroferric oxide with good dispersibility.(2)Using lipopolysaccharide to induce the inflammatory factor TNF-?(tumor necrosis factor)of macrophage RAW 264.7 cells,and to explore the effect of magnetocaloric effect on the surface of cell membrane on macrophage differentiation.In the previous trial,two superparamagnetic iron oxides(SPIOs)were tested for cytotoxicity to determine the safe concentration range at which the particles could be used.In this experiment,7 nm and 16 nm superparamagnetic iron oxide nanoparticles were adhered to the surface of the cell membrane after short-term incubation.When LPS induced macrophages,the external magnetic field was applied to induce the magnetocaloric effect on the surface of the cell membrane.The effect of macrophage polarization was observed.It was finally found that the 7 nm particle experimental group exhibited an inhibitory effect on the LPS-induced TNF-? effect under the action of an external magnetic field,and this effect was due to the magnetocaloric effect,not the particle itself.(3)In order to investigate whether the magnetocaloric effect in magnetic hyperthermia has an effect on macrophage polarization,we have studied the effect of magnetocaloric effects on macrophages polarization.Because in the magnetic hyperthermia of tumors,nanomaterials will remain in the tumor for a long time,and macrophages will engulf more nanomaterials.Therefore,this experiment allowed macrophages to be incubated with nanomaterials for a longer period of time,and Ferrimagnetic vortex-domain nanorings(FVIOs)with higher magnetocaloric efficiency were selected.It was finally discovered that macrophages were polarized by FVIOs themselves,which is consistent with previous reports,but its magnetocaloric effect,which is mediated by external magnetic fields,further strengthens the polarization of macrophages.(4)Magnetic hyperthermia treatment of a mouse breast cancer model was performed.The mouse was implanted with a 4T1 mouse breast cancer in situ tumor model,and after the tumor grew to a certain volume,FVIOs were injected intratumorally for magnetic hyperthermia.The results show that the effect of magnetic hyperthermia on tumors is very obvious.Subsequent trials will slice the tumor and perform immunohistochemistry to further investigate the polarization of its internal macrophages.