T1 MRI/荧光/CT成像三功能造影剂的制备及其应用研究

Multimodality imaging has become an inevitable trend of imaging diagnotics in clinical trials. Multifunctional contrast agents that meet the requirments of multimodal imaging are indispensable and play a vital role in the imaging quality. In this study, Gadolinium (Gd), Europium (Eu) and Iodine (I) containing polymerizable complex monomers are first designed and synthesized and then polymerized with other （functional）monomers to prepare monodispersed nanoparticles by microwave-assisted atom transfer radical emulsion polymerization. The obtained nanoparticles can be further utilized as T1 MRI/fluorescence/CT trifunctional imaging contrast agents. The facile and feasible method to prepare the trifunctional contrast agents will be investigated, overcoming the drawbacks of multistep synthesis and the difficulty in purification. The stable and uniform distribution of rare earth metals irons in the nanoparticles will be achieved and the leakage of rare earth metals irons will be minimized and avoided. Meanwhile, we will explore the preparation of small size (diameter smaller than 30 nm) monodispersed trifunctional contrast agents to expand their applications, such as the brain and cardiovascular angiography imaging. The interrelationship between structure and properties will be studied, together with the parameters and factors influencing the particle size and function. Moreover, systematical investigation of interaction mechanism between the nanoparticles with biomacromolecules and cells, and the applicationons in cell imaging and tumour diagnosis will be carrried out, providing innovative substances and theoretical basis for the development of multimodal imaging technology.

多模式成像是医学成像发展的必然趋势，而满足多模式成像要求的多功能造影剂是不可或缺的，对成像的质量起着关键作用。本项目拟设计合成含钆、含铕及碘的可聚合配合物单体，然后与其它（功能）单体通过微波辐射原子转移自由基乳液聚合，可控制备出小粒径、单分散纳米粒子作为T1 MRI/荧光/CT多模式成像三功能造影剂。探索出简单易行的三功能造影剂制备方法，克服制备步骤繁琐和不易纯化的缺点；实现稀土金属离子在纳米粒子中稳定、均匀分布，避免稀土物质泄露；解决制备小粒径（直径≦30nm）、单分散三功能造影剂的困难，从而拓展其在生物体内的应用范围，如脑部、心血管等特殊部位造影成像。研究三功能造影剂的结构、性能及其内在关系，探索粒子大小及功能可控的参数和条件；考察三功能造影剂与生物大分子、细胞的相互作用，探讨作用机理；研究其在细胞显影、肿瘤诊断等方面的应用，为多模式成像技术的发展提供创新的物质基础和理论依据。

满足多模式成像要求的多功能造影剂是不可或缺的，对成像的质量起着关键作用。本项目设计合成了含钆、含铕及碘的可聚合配合物单体，然后与其它（功能）单体通过原子转移自由基（乳液）聚合、无皂种子乳液聚合、自组装及生物矿化等技术，可控制备出小粒径、单分散纳米粒子作为多模式成像功能造影剂，如MRI/荧光/CT模式成像三功能造影剂、双荧光/CT/MRI模式成像四功能造影剂、T1-T2 MRI/荧光模式成像三功能造影剂等。探索出简单易行的多功能造影剂制备技术，实现了稀土金属离子在纳米粒子中稳定、均匀分布，避免稀土物质泄露。考察了多功能造影剂的结构、性能及其内在关系和粒子大小及功能可控的参数和条件；探究了多功能造影剂与生物大分子、细胞的相互作用，研究了其在细胞显影、肿瘤诊断等方面的应用。拓展了多模式成像引导光动、光热治疗的研究，并取得优良效果。重要研究结果如下：.（1）合成了含碘稀土配合物Eu(AA)2(DTA)Phen，并通过无皂乳液聚合法制备了核-壳结构三功能聚合物粒子。当碘附载量低于4.8 mgI/ml时，仍有明显CT造影效果；弛豫率为259.59 mM-1 S-1；在肝脏和脾脏组织中表现出明显红色荧光。.（2）通过自组装法制备了金属-多酚网状物包覆BaGdF5纳米粒子。可产生绿色（520 nm）和红色（590 nm）荧光，有很好的CT增强效应，体外和体内MRI均表现出增强的T1信号，纵向弛豫率r1 = 2.457 mM-1 s-1，具有作为双光学/CT/MRI四模态成像造影剂的潜力。.（3）通过无皂乳液聚合法制备了T1-T2磁性荧光三功能核-壳纳米粒子。可观察到鲜明的红色荧光，纵向弛豫率r1 = 8.39 mM-1 s-1，横向弛豫值r2 = 71.18 mM-1 s-1，体内外MRI均表现出增强的T1和T2信号。.（4）通过ATRP法，将含钆配合物 Gd(AA)3Phen接枝在硫化铅纳米粒子表面，制备出CT/MR成像引导的光热诊疗纳米粒子。粒径约为11 nm，光热转换率高达31%，体内外具有优异CT、MRI成像效果。.（5）通过ATRP法，将含铕、碘配合物Eu(AA)2(DTA)Phen接枝到经Cu2+催化氧化多巴胺纳米粒子表面，制备出CT/荧光成像引导的光热诊疗纳米粒子。具有优良的体内外CT/荧光成像造影效果，对肿瘤有明显的光热治疗效果。