功能化穴番超极化Xe-129分子探针的构建与性质研究

发布时间：2018-04-02 11:16

本文选题：核磁共振　切入点：穴番　出处：《中国科学院大学(中国科学院武汉物理与数学研究所)》2017年博士论文

【摘要】：~（129）Xe是一种无毒无害的气体,对化学环境敏感,且超极化~（129）Xe具有较高的磁共振灵敏度,因此其在生物医学领域有巨大的应用价值。但是超极化~（129）Xe直接作为分子探针存在无靶向性的缺点。利用一种与~（129）Xe具有较高亲和力的笼状化合物穴番作为~（129）Xe的主体分子,对笼状化合物穴番进行功能化的修饰,可以赋予~（129）Xe靶向性。本文在前人的研究基础上,设计合成了一系列功能化的穴番化合物,然后利用超极化~（129）Xe磁共振、光谱等手段较为详细的研究了各化合物的性质。其中部分性质良好的化合物,可作为分子探针实现对生物活性物质的特异性探测。主要研究内容及实验结果包括以下几部分:1.构建了可特异性识别硫醇的穴番化合物。该化合物由三部分组成:~（129）Xe磁共振报告单元穴番、荧光报告单元萘酰亚胺、可对硫醇响应的二硫键。硫醇在生命活动中扮演着重要的角色,因此实现对其高灵敏的探测具有十分重要的意义。我们所构建的化合物对硫醇显示出了较高选择性,并且在较宽pH范围内的稳定性良好,可在细胞内实现对硫醇的检测。我们分别用荧光以及~（129）Xe磁共振的方法实现了对细胞内硫醇的检测。本研究工作发展了一种检测细胞内硫醇的方法,利用超极化技术实现了对细胞内硫醇的高灵敏检测。2.构建了一种硫醇响应的穴番药物监测系统。该药物监测系统由四部分组成:~（129）Xe主体分子穴番、荧光报告单元萘酰亚胺、可对硫醇响应的二硫键、以及抗癌药物苯丁酸氮芥。该化合物对硫醇显示出了较高的选择性,在硫醇的作用下,可缓慢的释放出苯丁酸氮芥。我们利用荧光以及~（129）Xe磁共振的方法对药物的释放过程实施监测,两种方法所得结果一致。苯丁酸氮芥在癌细胞中被有效释放,对肺癌细胞显示出一定的杀伤作用。本研究工作提供了一种药物监测系统的设计方法,首次将~（129）Xe磁共振应用到药物的释放监测中。3.构建了一种小分子多功能穴番化合物。该化合物由两部分组成:~（129）Xe主体分子穴番、具有多种功能的卟啉基团。该化合物在较宽pH范围内可对pH的变化做出高灵敏的响应,并且在细胞中也可对pH的变化做出响应。在生理条件下该化合物能通过光照产生单线态氧,有用于光动力学治疗的潜力。激光共聚焦实验证明了该化合物对癌细胞有较好的靶向性。因其荧光较强,发射波长较长,能有效用于活体荧光成像。
[Abstract]:Xe is a non-toxic and harmless gas, which is sensitive to chemical environment and has high magnetic resonance sensitivity. Therefore, it has great application value in biomedical field. However, it has the disadvantage of not targeting directly as a molecular probe. A cage compound with high affinity to Xe is used as the host molecule of Xe. In this paper, a series of functionalized cavernous diophane compounds were designed and synthesized on the basis of previous studies, and a series of functional compounds were synthesized by using hyperpolarimetric 129Xe magnetic resonance resonance (Mr). The properties of various compounds have been studied in detail by means of spectra and other means. Some of them have good properties. It can be used as a molecular probe to detect bioactive substances. The main research contents and experimental results include the following parts: 1. A specific thiol recognition compound was constructed. The compound consists of three parts. The report unit of Xe magnetic resonance is 129e. Fluorescent reporting unit naphthalimide, a disulfide bond that responds to mercaptan. Mercaptan plays an important role in life activities. Therefore, it is of great significance to achieve a highly sensitive detection of mercaptan. Our compounds exhibit high selectivity to mercaptan and have good stability in a wide pH range. The detection of mercaptan can be achieved in cells. We have developed a method for the detection of intracellular mercaptan by fluorescence and magnetic resonance spectroscopy (MRI). A highly sensitive drug monitoring system for mercaptan response was constructed by using hyperpolarization.2.The drug monitoring system consisted of four components, the main molecule of 1: 129Xe, and the fluorescent reporting unit, naphthalimide. The thiol responsive disulfide bond, as well as the anticancer drug phenylbutyrate nitrogen mustard, showed a high selectivity to mercaptan. Phenylbutyrate nitrogen mustard can be released slowly. We monitor the release process of the drug by using fluorescence and 129Xe magnetic resonance. The results of the two methods are consistent. Phenylbutyrate nitrogen mustard is effectively released in cancer cells. This study provides a method for the design of a drug monitoring system. For the first time, the magnetic resonance (Mr) of 129Xe was applied to the monitoring of drug release. 3. A multifunctional compound of small molecules was constructed. The compound is composed of two parts, the main molecule of Xe is composed of two parts, one is the main molecule of Xe, and the other is the main molecule of Xe, which is composed of two parts. A porphyrin group with many functions. The compound can respond to the change of pH in a wide range of pH. It also responds to changes in pH in cells. Under physiological conditions, the compound produces singlet oxygen through light. Laser confocal experiments show that the compound has good targeting to cancer cells. It can be effectively used for in vivo fluorescence imaging because of its strong fluorescence and long emission wavelength.
【学位授予单位】：中国科学院大学(中国科学院武汉物理与数学研究所)
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O657.3

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