Design,Synthesis And Biomedical Applications Of Gd Complex-based Magnetic Resonance Imaging Contrast Agents

With the growing use of magnetic resonance imaging(MRI)in clinical diagnosis,the demand for MRI contrast agents is dramatically increasing.In the face of some shortcomings of current clinical contrast agent exists,the design of high-performance MRI contrast agent has become more and more important in the field of molecular imaging.In this thesis,based on the clinical small molecular contrast agent,several new MRI contrast agents with good biocompatibility are explored to serve as high-performance contrast agents for effective contrast-enhanced MRI in biomedical fields.In Chapter 1,we briefly reviewed the key factors and research progress of T1 magnetic resonance imaging contrast agents,and also demonstrated the selection basis and research content of this thesis.In Chapter 2,based on SBM theory,prolonging the rotatinal correlation time can improve the T1 relaxivity,we constructed a multiple gadolinium complex decorated fullerene(CGDn)as an enhanced T1 contrast agent.The CGDn exhibits good biocompatibility,and shows excellent T1 contrast enhancement ability in magnetic resonance angiography.In Chapter 3,based on amphiphilic molecules with aromatic ring can nonspecificly interact with albumin,we synthesizd an albumin-targeted amphiphatic molecular contrast agent Ibu-Gd.Ibu-Gd can targetedly bind to human serum albumin to improve T1 relaxivity and show excellent T1 blood vessel contrast enhancement ability in vivo,illustrating that this small moleculecan serve as a potential blood pool contrast agent.In Chapter 4,we synthesized a novel albumin-based nanoprobe loaded with ibuprofen-modified gadolinium chelates,named Ibu-Gd-BSA nanoparticles(NPs).It was verified that Ibu-Gd-BSA NPs exhibited an extremely high relaxivity,along with long-term stability and good biocompatibility in vitro and in vivo.Due to the long blood circulation half-life and high accumulation in tumor,Ibu-Gd-BSA NPs have the great potential for tumor imaging and diagnosis by contrast-enhanced MRI.In Chapter 5,based on good biocompatibility and improved T1 relaxivity of albumin nanoparticles,we designed and synthesized Glycyrrhetinic acid-modified Gd-DOTA derivatives(GGD),which further bind with BSA to form nanoparticles by cross-linking(GGD-BSA NPs).By controling the different precursor molar ratios,we obtained several sizes of GGD-BSA NPs to explore the relationship of component and relaxivity.Benifiting from enhanced T1-T2 dual modal MR contrast ability at high magnetic field,these GGD-BSA NPs enable noninvasive detection of liver tumors with high accuracy.In Chapter 6,to conduct the integration of diagnosis and treatment,we explored the molar ratios of GGD,ICG molecules,and human serum albumin for self-assembly,and obtained the HSA-GGD-ICG nanocomplex.Compared with small molecules GGD and ICG,HSA-GGD-ICG has higher T1 contrast ability,stronger fluorescence signal,and more effective photothermal conversion capability.In vivo experiments proved that HSA-GGD-ICG has great capability for the dual-model MRI/FL guided photothermal therapy and monitoring the tumor ablation in real time.