针对淀粉样变的多功能分子靶向显影剂的基础研究

Amyloidosis is a progressive, incurable, metabolic disease characterized by abnormal deposits of protein in one or more organs or body systems, which can cause organ failure or death. Its characteristic pathology is amyloid which can be stained with Congo red. The only way to make a definitive diagnosis for amyloidosis is to use a biopsy of the organs. The lack of effective diagnosis by noninvasive techniques is a key factor which canses the resluts that the diseases cannot be treated timely. In this study,a new bifunctional molecular probe based on Congo red which can target amyloidosis, 125I-Albumin-(Gd-DTPA)n-CR, is synthesised. The high spatial resolution of MR and the high sensitivity of SPECT is integrated with the probe.And quantitative diagnosis, qualitative diagnosis and location of the lesions is determined with the probe. The amyloid of the heart, liver, spleen,kidney,and etc, can be displayed effectively with the multifunctional probe. The basic imaging mechanism and metabolism in vivo of the probe is studied, which can provide an important technology for detection of amyloidosis in vivo, and provide an important substance for further study of primary and secondary amyloidosis's pathogenesis.

淀粉样变是多种病因引起的蛋白质代谢障碍的重要转归之一，可累及全身多个器官，导致器官衰竭。其特征性病理表现是形成可以被刚果红染色的淀粉样物质。确诊需要组织活检，临床上缺乏有效的无创显示和诊断方法是本病得不到及时治疗的关键因素。本研究以白蛋白为载体合成一种新的基于刚果红的靶向淀粉样病变的双功能分子探针125I-Albumin-(Gd-DTPA)n-CR，将MR的高空间分辨率与SPECT的高灵敏度结合，实现定位、定性及定量诊断一体化，有效显示皮下淀粉样瘤、心、肝、脾、肾等脑外淀粉样病变，通过对该系列分子探针的基本成像机理和体内代谢过程的研究为活体检测淀粉样变提供重要的技术手段，为进一步研究原发及继发性淀粉样变的发病机制提供了重要的物质基础。

项目背景：淀粉样变是多种病因引起的蛋白质代谢障碍的重要转归之一，可累及全身多个器官，导致器官衰竭。其特征性病理表现是形成可以被刚果红染色的淀粉样物质。确诊需要组织活检，临床上缺乏有效的无创显示和诊断方法是本病得不到及时治疗的关键因素。.主要研究内容：第一部分为针对外周脏器系统性淀粉样变性的双模态纳米靶向探针BSA- (Gd-DTPA)n-CR-Tc的合成、表征及初步评价。目的是在前有的研究基础上，优化BSA-(Gd-DTPA)n造影剂的合成分离及纯化方法,进而合成以刚果红为靶向头基的磁共振探针前体BSA-(Gd-DTPA)n-CR，初步评价其体外弛豫性能及大小。取第一部分合成并纯化好的BSA-(Gd-DTPA)n备用。刚果红与NHS-PEG-MAL的比例为1:1，BSA-(Gd-DTPA)n巯基化后与刚果红的比例为1:20，在PH=7.4的PBS缓冲体系中反应生成BSA-(Gd-DTPA)n-CR。分离纯化后进行锝的标记，再行分离。尾静脉给药后于不同时间点进行核磁共振及SPECT/CT成像，评价双模态造影剂用于正常及模型小鼠MR及SPECT/CT的成像情况。第二部分为外周脏器系统性淀粉样变性的双模态纳米靶向探针BSA-(Gd-DTPA) n-P5-Tc的合成、表征及初步评价。合成AA型淀粉样变性的磁共振靶向探针BSA-(Gd-DTPA) n-P5，评价其体外弛豫性能、对小鼠外周脏器淀粉样变性的显示能力，再进行锝的标记。对靶向探针BSA-(Gd-DTPA) n-P5-Tc进行表征。. 重要结果：探针BSA-(Gd-DTPA) n-P5-Tc和BSA- (Gd-DTPA)n-CR-Tc均显示了不同程度的AA淀粉样变性的亲和力和靶向性，对照探针组、模型前体组和模型探针组之间显示出了核素滞留率的差异，磁共振检查虽然特异性较高，但是敏感性较SPECT为低，所以将两者相结合的双模态显像提高了淀粉样变性显示的敏感性、特异性，提高了检出率。