Increasing The Relaxivity Of T₁ MRI Contrast Agents By Self-Assembly Strategy

Magnetic resonance imaging?MRI?is a non-invasive medical imaging diagnostic technique and was first applied to human in the 1970s.MRI has captured widespread attention from investigators in the field of molecular imaging due to its unique advantages of high spatial resolution,sharp permeability of deep tissues,and the absence of ionizing radiation.With the objective of improving the clarity and contrast of imaging,gadolinium-based MRI contrast agents are used to increase the relaxation rate and shorten the relaxation time of protons.However,there is an increasingly demand for new MRI contrast agents with high relaxivity and well security because the commonly used small-molecule agents?e.g.Magnevist,Prohance?are generally deficient such as low relaxivity,poor selectivity,and modest imaging capability.The relaxivity can be improved by linking small molecule contrast agents with polymer covalently.However,the preparation of macromolecular contrast agents is generally complex and macromolecular contrast agents may have cumulative toxicity due to the difficulty of metabolism after imaging.Thus,the self-assembly strategy was used to increase relaxivity for amphiphilic Gd-based contrast agents in this thesis.The formation of micelles triggered an abrupt upgrade in relaxivity and the noncovalent connections were preferential regarding to the rapid elimination of Gd???ions from the body through disassembly.The basic principle of magnetic resonance imaging was introduced in chapter?of this thesis.According to SBM theory,the strategies to increase relaxivity were discussed by enlarging the coordinated water of inner sphere and enhancing the rotational correlation time.Then,the current research status of amphiphilic Gd-based MRI contrast agents was introduced.The synthesis of the neutral amphiphilic Gd-based chelates modified by different lengths of alkyl chains was described in detail in chapter?,then the morphology and stability of relevant self-assembled micelles were studied at the same time.In chapter?,the relaxation measurement and in vitro imaging were carried out for the four neutral micellar agents,and their safety properties were evaluated through in vitro transmetalation,xylenol orange test for free Gd³⁺and cytotoxicity.The micellar contrast agents of Gd?HP-DO3A?-C₁₆ produced via self-assembly strategy displayed an efficient relaxivity up to 14.5 mM^-1s^-1?128MHz,25??,extremely low critical micelle concentration?30?M?,excellent water solubility?60 mg/mL?and sufficient safety,which had a significance for the development of new high-performance and safe clinical MRI contrast agents.