Preparation And Application Of Gadolinium-Based Contrast Agents For High-Contrast Magnetic Resonance Imaging

Magnetic resonance imaging(MRI)is a clinically highly-dependent medical diagnostic equipment,which provides excellent accuracy and flexibility for the diagnosis of internal diseases of the human body.With the increasing demand for early diagnosis and accurate detection of various diseases,MRI has become an essential diagnostic tool in all major hospitals.The improvement of MRI technology also inspires the rapid development of various contrast enhancement techniques.However,the developed T1-weighted,T2-weighted and T1-T2 dual-mode contrast agents are not satisfactory,and their respective inherent limitations have aroused the interest of researchers in developing various types of MRI contrast agents.Here,this thesis is based on the high-contrast gadolinium-based MRI contrast agents,and has carried out some new explorations,the specific contents are as follows:First,to significantly improve the MRI contrast between tumor and normal tissues,a new concept of contrary contrast MRI(CC-MRI)is proposed.CC-MRI contrast agents show positive or negative signals in normal tissue,but show opposite signals in diseased tumor tissue.To achieve CC-MRI of tumor tissue,a tumor microenvironment GSH/pH dual-responsive contrast agent(SA-FeGdNP-DOX@mPEG)is developed.Through a single sequence of scans,the tumor and liver signals show a positive and negative contrary effect,resulting in ultra-high contrast MRI images.The difference between the two signal-to-noise ratios is 501%,which effectively achieves CC-MRI.Moreover,SA-FeGdNP-DOX@mPEG has the function of an intelligent "switch" of MRI signal and controllable drug release,which can be used for high-performance tumor diagnosis and chemotherapy.Therefore,high-contrast single-mode CC-MRI is a new imaging mode and an effective breakthrough in the field of MRI contrast agents.Secondly,to address the major problems of commercially available smallmolecule gadolinium chelates and reported gadolinium-based contrast agents,we develop a new type of macromolecule gadolinium chelates(OGMCs)with weak ferromagnetic properties(i.e.,Gd-PAA and Gd-PASP).The OGMCs Gd-PAA and GdPASP have ultra-high r1 values(>50 mM-1 s-1)and ultra-low r2/r1 ratio(<1.6,3.0 T),which significantly improve the contrast of MRI in T1-weighted imaging and are excellent T1-weighted contrast agents.Gadolinium-based contrast agents widely used in the clinic and reported in the literature are all paramagnetic,while the OGMCs developed in this study are weakly ferromagnetic(Ms<1.0 emu/g)and are completely new gadolinium-based contrast agents.The MR imaging window of OGMC s is slightly longer than the small molecule gadolinium chelates,shorter than that of nanoparticles,and more suitable for the clinical MRI application scenario.The results of cell and animal experiments confirm that the OGMCs have good biosafety and excellent T1weighted MR imaging capability.Moreover,the synthesis method of OGMCs is simple and easy to enlarge the production.Thus,OGMCs Gd-PAA and Gd-PASP can serve as superior T1-weighted MRI contrast agents with promising commercial transformation potential.