基于Mn2+的两亲性高效能T1磁共振血池造影剂

Based on our previous catechol-EDTA manganese(II) complex work， a new kind of amphiphilic blood pool MRI contrast agent was designed by introduce hydrophobic long chains like perfluorine carbon chain considering the safety problem of nephrogenic systemic fibrosis(NSF) related to the clinical used gadolinium contrast agents. In aqueous solution, this amphiphilic molecule can self-assembly efficiently to form micelle or liposome with very low critical micelle concentration(CMC) or binding to the extracellular matrix(ECM) like HSA with high affinity to form HSA@Mn-EDTA comlex. The global rotational motion (Tau_Rg)was efficiently slow down by the formation of micelle or HSA@Mn-EDTA complex and also the local rotational motion(Tau_Rl)of the paramagnetic center was restricted. This lead to the above amphiphilic molecules a new kind of non-gadolinium MRI contrast agents with high relaxivity and long blood circulation half-life. The diseases like atherosclerosis, the vascular endothelial integrity was damaged and the permeability increased. The amphiphilic contrast agent especially the molecule with the super-hydrophobic and super-lipophobic perfluorine chains can penetrate the lesion while bound to HSA and then accumulate within the extracellular, fibrous parts of the AS plaque by binding to collagens, proteoglycans and tenasin, which have the same affinity to these plaque constituents as to albumin. Based on this hypothesis, we will perform the research on the synthesis, important physical and chemical parameters characterization and pharmacology of the new amphiphilic contrast agent. The research of the MR molecular imaging to detect the AS plaque will also be conducted by using this new contrast agent.

针对临床钆类造影剂的肾源性系统纤维化风险， 在本课题组已完成的具有邻苯二酚结构的类Mn-EDTA配合物基础上，通过引入疏水长链设计了一类新型两亲性Mn(II) T1磁共振血池造影剂。 在水溶液中，该两亲性分子可高效自组装形成纳米胶束或者与细胞外间质如血清白蛋白（HSA）等高亲和力结合形成复合物，从而有效降低Mn(II) 造影剂端在溶液中的旋转回复时间，极大地提高单位锰造影剂的弛豫效率，得到一种高灵敏度的长血液循环半衰期非钆类血池造影剂。该两亲性造影剂进入体内与HSA结合形成HSA@Mn-EDTA复合物后，具有长循环、高灵敏度、在血液中不能透过正常血管内皮的特点， 有利于MRI显示血管内皮完整性发生破坏或通透性增加的病变（如AS、炎症及肿瘤） 。我们拟开展不同疏水结构两亲性Mn(II)造影剂合成制备及其关键物理化学参数表征、药理学研究以及该造影剂用于AS斑块的MRI分子影像研究。

在本项目资助周期内（2017年1月-2020年12月），按计划完成了项目计划书中“基于 Mn2+两亲性高效能 T1 磁共振血池造影剂”的合成、表征以及动物体内成像等研究。.在开展上述研究过程中，利用关键中间体配体结构可做多种修饰的特点，通过结构修饰来调节造影剂的体内分布代谢行为，实现体内酶响应、靶向特定受体分子的目的。围绕核心结构 Mn-TyrEDTA，我们同时开展了 “肝胆特异磁共振造影剂”、“MPO 响应磁共振探针”、“靶向乏氧实体瘤 CA IX磁共振探针”、“T1/T2 双模式磁共振造影剂”等方向的研究。上述基于 Mn(II)磁共振造影剂的研究，为克服钆基造影剂“肾源性系统纤维化”和“钆离子脑沉积”安全性问题提供了潜在的解决方案，为体内酶响应和肿瘤靶向性磁共振探针的研发奠定了基础。特别是针对易损斑块的病理结构特征和炎症反应特点，两亲性血池造影剂可用于”薄帽“斑块的诊断；MPO 响应磁共振探针可用于评估斑块的炎症反应程度。