Design And Synthesis Of Magnetic Nanomaterials For Contrast-Enhanced MRI And Tumor Theranostics

Magnetic nanomaterials have a wide range of applications in biomedical applications due to their good biocompatibility,easy surface modification,and controllable size and morphology.Magnetic resonance imaging(MRI)is unique in the diagnosis of tumors due to its advantages of no radiation,breakable tomography,etc.,and has also attracted the attention of researchers.However,commercial contrast agents(CAs)have been suffering from low relaxation,potential toxicity.Therefore,the development of nanomaterials combined with the diagnosis and treatment of tumors are of great practical significance.Based on this,we designed and synthesized a variety of CAs based on iron oxide and manganese oxide nanomaterials,which has good biocompatibility and significantly enhanced magnetic resonance imaging performance.We have also studied their application in the diagnosis and treatment of soild tumors.The main research contents are summarized as follows:In Chapter 1,we briefly introduced the research progress of magnetic nanomaterials in the diagnosis and treatment of tumors.We also outlined the basics of MRI,including the development of magnetic resonance imaging,principles and MRI CAs.The topic and main research contents of the doctoral thesis are put forward.Iron oxide nanomaterials have been intensively investigated over the past decades as MRI contrast agents due to their favorable magnetism and excellent biocompatibility.However,commercial iron-oxide-nanoparticle-based CAs suffers from low T2 relaxivity,which significantly limits their applications in biomedical fields.Herein,in Chapter 2,we reported a new type of iron oxide nanoplates(IOPs)with an interesting twinning plane,which are fabricated via seed growth.Compared with the conventional iron oxide(10)spherical nanoparticles,iron oxide twin nanoplates(IOP-13)have larger effective radius,higher saturation magnetization,and greater anisotropy,resulting in their superior T2 relaxivity of 571.21 mM-1 s-1 at 0.5 T,which is about six times higher than that of commercial IO nanoparticles.In vivo MR imaging demonstrated that IOP-13 could be used for liver imaging and liver tumor diagnosis with high sensitivity and accuracy,revealing the great potential of IOP-13 as next-generation CAs.For in vivo imaging,it is important that imaging agents could be harmlessly eliminated from the body after performing their functions.The excellent biocompatibility and biodegradability of y-Fe203 nanoparticles render them promising as a potential candidate for T1 contrast agents.Herein,in Chapter 3,we developed a facile synthesis of biodegradable hollow porous iron oxide nanoboxes(HPIOs)with high r1 values and low r2/r1 ratios,allowing for superior contrast-enhanced T1 imaging.The zwitterionic dopamine sulfonate(ZDS)functionalized HPIOs(HPIOs@ZDS)could effectively avoid nonspecific protein adsorption and achieve controllable biodistribution.Furthermore,HPIOs@ZDS could be degraded into 4-5 nm fragments in the body and subsequently cleared by kidneys rapidly after in vivo imaging,which significantly reduces potential long-term toxicity.These desirable features make HPIOs@ZDS a prominent T1 contrast agent for magnetic resonance angiography in vivo.These biodegradable and biocompatible HPIOs@ZDS holds great promise for highly sensitive and accurate detection of heart and vascular diseases in molecular imaging.Multifunctional nanoparticles with integration of diagnostic and therapeutic functions have received extensive attention in tumor imaging and therapy.The stimuli-responsive nanoparticles as a smart carrier nanoplatform is of urgent demand.Manganese oxide nanoparticle can enhance T1 MR signal by decomposing Mn ions in response to low pH value.Herein,in Chapter 4,we reported that octapod-shaped hollow porous manganese oxide(HPMO)nanoparticles as a stimuli-responsive T1 activitable nanoplatform for cargo delivery and real-time monitoring in vitro and in vivo.HPMO can act as a versatile platform to load organic dyes or chemotherapy drugs,e.g.,doxorubicin,Rhodamine 123,and camptothecin.After endocytosis by tumor cells,the obtained Cargo@HPMO can decomposed into paramagnetic Mn2+ions,meanwhile releasing cargos.The released Mn2+can light-on the MR signal for real-time monitoring the delivery process of cargos.Finally,we demonstrated that DOX@HPMO nano-platform can effectively target tumor tissue by enhanced permeability and retention(EPR)effects,and achieve tumor-specific imaging and real-time monitoring of drug release in vivo.Compared to free DOX,DOX@HPMO shows enhanced anticancer therapeutic efficacy without side effects due to increased DOX enrichment in tumor and reduced accumulation of normal tissues.This strategy that accomplishes real-time multimodal monitoring of drug release via pH responsive T1 MR and fluorescence imaging is of significant importance and impendency for accurate diagnosis and precise therapy in clinical applications.In conclusion,we synthesized MR contrast agents based on iron oxide and manganese oxide nanomaterials,and inverstigated their MRI performance and diagnosis and treatment of tumor.Although these research contents enrich the magnetic resonance contrast agent,there are still some deficiencies.The formation mechanism of nanomaterials and the contrast enhancement performance of magnetic resonance remain to be further explored.