Research Of Synthesizing Iron-based Magnetic Resonance Imaging Contrast Agent And Their Application In Tumor Diagnosis And Therapy

Cancer is still one of the most devastating and fatal diseases in the world,and early diagnosis of cancer is a prerequisite for early treatment.Magnetic resonance imaging(MRI)has high soft tissue resolution and high tissue penetration,and has been widely used in cancer diagnosis as a non-invasive and non-radiation technology.For high-quality imaging,intelligent contrast agents with low toxic side effects and high relaxation properties have always been sought after.The long-term biocompatibility of iron has made iron oxide nanoparticles a research hotspot for MRI contrast agents.At the same time,the magnetocaloric effect of iron oxide can effectively combine MR imaging with magnetic hyperthermia.Therefore,the main research purpose of this thesis is to prepare smart iron-based contrast agents with high relaxation properties and to study their applications in MR imaging and cancer therapy.The research of this thesis is mainly divided into two parts:the first part is the synthesis of p H-responsive iron oxide nanoclusters and its application in MR imaging;the second part is the synthesis of GSH-responsive core-shell iron oxide nanoparticles,And its application in multimodal imaging and magnetic hyperthermia.The main work done by the author is as follows:(1)We propose a method for synthesizing iron oxide nanoclusters with a hydrodynamic size of about 148nm.First,10nm superparamagnetic iron oxide nanoparticles(SPION)were prepared by co-precipitation method,and citric acid was used to modify the surface.After the methoxy polyethylene glycol(mPEG)is connected with 4-formylbenzoic acid(FBA)as a side chain,it is connected to polylysine(PLL)through a p H-responsive benzoic imine bond to form an amphiphilic polymer(PLL@mPEG),then PLL@mPEG and Fe₃O₄are connected via an amide bond,then transferred to the water and form p H-responsive nanoclusters PLL@mPEG@SPION by self-assembly.PLL@mPEG@SPION and their p H-response were characterized by series of tests(TEM,FTIR,DLS).The results show that the PLL@mPEG@SPION nanoclusters can be redispersed into relatively dispersed iron oxide nanoparticles at p H=6.0.MRI results prove that the PLL@mPEG@SPION has better T₂imaging performance and higher relaxation rate(r₁=3.47 m M^-1s^-1,r₂=301.53 m M^-1s^-1,r₂/r₁=38.08,on 1.5T).However,the magnetic thermal performances of PLL@mPEG@SPION are poor,which leads to the poor magnetic hyperthermia effect of tumors.(2)In order to improve the effect of magnetic hyperthermia on tumors,a core-shell structure MFe₃O₄@DOX@Mn O₂composite nanoparticle was further developed.The core was mesoporous Fe₃O₄and coated with Mn O₂.Its magnetic thermal performances can be used in magnetic hyperthermia.It was used as a carrier to load the chemotherapeutic drug doxorubicin(DOX).The use of magnetic hyperthermia in combination with chemotherapy enhances the effect of tumor therapy.Mn O₂released Mn²⁺after the reduction of glutathione(GSH)can be used for T₁imaging to realize the integration of diagnosis and therapy.The complex-co-precipitation method was used to synthesize mesoporous iron oxide(MFe₃O₄)with an average particle size of 30 nm.The surface was coated with Mn O₂through a redox reaction to synthesize nanoparticles with core-shell structure MFe₃O₄@Mn O₂.MFe₃O₄has a good mesoporous structure with a pore size of about3nm,it was characterized by TEM and BET.The magnetic thermal performances analyzed by Magne Therm.MFe₃O₄@Mn O₂has higher temperature than MFe₃O₄under AMF,which proves that coating MnO₂ to form a core-shell structure can significantly improve heating efficiency.The saturation magnetization was measured by VSM.No significant effect of Mn O₂on the saturation magnetization of MFe₃O₄was observed.The mechanism of improving heating efficiency needs to be further explored.A nanomedicine carrier with magnetic hyperthermia ability has been constructed,and it is ready for the next step of carrying DOX,exploring T₁imaging under GSH reduction,and the effect of tumor treatment.