适配体靶向的纳米载体的钆基磁共振成像造影剂的构建研究

MRI provides a three-dimensional and non-invasive imaging which has been widely used in cancer imaging. In order to enhance the detecting sensitivity and characterize the pathological abnormalities, contrast agents are used increasingly in diagnostic magnetic resonance imaging. In fact, it has been estimated that nearly 50% of all MR examinations already involve the use of contrast agents, with chelated gadolinium compounds being by far the most widely used. So far, the combination of nanotechnology and medical imaging contrast agents have profoundly promoted the development of the multifunctional device platforms. In order to obtain a new type of contrast agent with high sensitivity and targeting efficiency, in this project, the novel multifunctional gold and ZnO nanorods-based contrast agents simultaneously modified with gadolinium-conjugated dendrimer and aptamer against Her2 will be fabricated, which can deliver Gd-DTPA to the tumor area and achieve the early diagnosis of breast neoplasm. The Gd(Ⅲ) modified on the surface of dendrimer could facilitate the fast exchange between contrast agent-coordinated water molecules and water in the bulk solvent, and enhance the relaxivity. Then, we will investigate the nanoparticles' proper synthetic routes, surface modification and targeting ligands to obtain excellent MRI effect, especially the relation between the generation of dendrimer and the relaxivity of the nanoparticle. Finally, based on the aptamer against HER2, the initiative targeting efficiency of MRI and its dynamic distribution in vivo will also be investigated. This study will open a new field for developing new types of contrast agents based on different aptamers and promoting the disease early clinic diagnose and therapy.

为了提高钆基MRI造影剂的弛豫率及对肿瘤组织的造影成像能力，获得高灵敏、高特异性的肿瘤靶向磁共振造影剂，以实现癌症的早期诊断，本项目以造影剂弛豫理论为依据，设计和制备高弛豫率的基于适配体靶向的树形高分子-纳米棒载体的钆基MRI造影剂。在合成的低代树形高分子表面交联DTPA-Gd，满足与水分子的快速交换；将交联有DTPA-Gd的树形高分子组装到金纳米棒或ZnO纳米棒表面，可满足钆的有效负载量及机体对载体的尺寸要求；交联上HER2靶向的适配体，可实现HER2阳性的乳腺癌组织的富集。并系统地对构建的造影剂的MRI效果在细胞水平和活体水平上进行测试和评估。以求探索出构建高弛豫率基于靶向纳米载体的钆基MRI造影剂的一般规律和内在机理，为构建基于核酸适配体靶向不同癌组织的高灵敏MRI造影体系的普适方法提供理论依据和实验基础。

为了提高钆基MRI 造影剂的弛豫率及对肿瘤组织的造影成像能力，获得高灵敏、高特异性的肿瘤靶向磁共振造影剂，以实现癌症的早期诊断，本项目以造影剂弛豫理论为依据，设计和制备高弛豫率的基于适配体靶向的树形高分子-纳米棒载体的钆基MRI 造影剂。在项目执行过程中，我们进一步完善实验方案，对项目进行适当的调动，以提高其体内体外性能。比如我们将尺寸更小的金纳米粒子（13 nm）替换金纳米棒；用硫辛酸修饰的赖氨酸树形分子替代项目中胱胺为核的聚酰胺胺树形分子，以提高配体与纳米金的结合能力和生物相容性，相关实验结果准备投稿中。另外，在青年基金的支持下，我们还系统研究了基于壳聚糖、聚天冬氨酸、可还原裂解高分子、胶束等大分子MRI造影剂的肿瘤靶向效果；除了适配体靶向外，我们还研究了叶酸及cRGD靶向的MRI造影剂在肿瘤处的富集效果。.通过三年来对MRI造影剂的系统研究，课题组成功地建立了材料合成体系、细胞及动物水平检测方法；制备出几种MRI造影剂分子，构建适配体、叶酸及cRGD靶向的MRI造影剂，并系统地研究了其体内体外的相关性质；整个青年基金支持期间发表SCI论文共十篇，申请专利三个，培养硕士生四名（其中已毕业三名），培养博士生一名。因此，在青年基金的支持下，我们出色地完成了基金的相关内容。