基于环金属化铱（Ⅲ）配合物传感器的开发及对肿瘤标志物检测的应用研究

Many types of cancer are associated with high mortality rates due to lack of available detection methods for cancer biomarkers. By the time that observable symptoms of the tumor are presentable, the cancer has often metastasized, leading to significantly worse prognosis. Therefore, the development of detection methods for cancer biomarkers is of high importance for the early diagnosis of cancer. However, existing methods for cancer biomarker detection suffer from low sensitivity and selectivity, or complicated and costly sampling protocols. Cyclometalated iridium(III) complexes have attracted due to their attractive photophysical properties. In this proposal, we will develop iridium(III) complex-based sensors with recognition units for different cancer biomarkers for the purpose of constructing detection platforms for cancer biomarkers in biological samples and living cells. Firstly, a variety of C^N and N^N ligands will investigated to generate a library of iridium(III) complexes with different recognition units. Secondly, we will rationally investigate the relationship between ligand structure and the photophysical and recognition properties of the iridium(III) complexes. Thirdly, the iridium(III) complexes will be tested for their ability to detect cancer biomarkers in biological samples and living cells using time-resolved luminescence spectroscopy. This project not only explores new methods for the detection of cancer biomarkers, but combines expertise from chemistry, biology, medical science, among other fields, to generate results with important academic and practical significance.

癌症早期诊断技术的缺乏是癌症患者死亡率居高不下的主要原因之一。肿瘤标志物的检测为癌症早期诊断的实现提供了可能，但是现有方法仍在灵敏度、选择性等方面具有一定的局限性，无法满足临床诊断的需求。同时，环金属化铱（Ⅲ）配合物具有发光效率高、发光寿命长等优势，在荧光分析领域中受到极大的重视。本项目中，我们基于前期工作，拟开发一系列具有肿瘤标志物识别功能的铱(Ⅲ)配合物传感器，并构建检测肿瘤标志物的分析平台。首先，对铱（Ⅲ）配合物的配体进行结构修饰，建立一个结构多样化的C^N配体库和具有肿瘤标志物识别功能的N^N配体库。其次，考察配体结构与铱（Ⅲ）配合物性质之间的关系，建立配体选择标准。然后，使用时间分辨法构建生物样品中肿瘤标志物的分析平台。最后，将该平台应用于细胞中肿瘤标志物的检测。本项目为肿瘤标志物的检测提供了新思路，有效地促进化学、生物、医学等多学科的交叉融合，具有重要的学术意义和潜在应用价值。

肿瘤标志物和早期癌症密切相关，在早期癌症诊断方面具有重要意义。但是现有诊断方法在灵敏度、靶向性等方面都存在一些不足，临床应用受限。近年来，铱配合物在肿瘤标志物检测中受到关注，但是仍缺乏一个通用的构建策略，且大多铱配合物肿瘤靶向性较差。本项目研究内容主要基于N^N配体，通过结构修饰连接肿瘤标志物识别分子，构建了多种肿瘤标志物检测发光探针，充分利用铱配合物独特的光物理性质，实现了多种肿瘤标志物的特异性检测：1）合成了一系列N^N配体中包含组蛋白去甲基化酶1（LSD1）抑制剂的铱配合物，总结了配体结构与配合物光学性质之间的关系，运用该类探针成功区分宫颈癌细胞HeLa和正常细胞LO2；2）合成了一系列N^N配体中包含多巴胺受体激动剂的铱配合物，总结了配体结构与配合物光学性质、对多巴胺受体靶向性之间的关系，运用时间分辨技术在肺癌细胞中实现低背景检测多巴胺受体。本项目的成功实施为铱配合物检测探针提供了一种通用构建策略，扩展了这类新型探针在生物医学领域的应用，解决了小分子荧光探针光稳定性差、荧光寿命短等问题，是研究肿瘤发生机制和癌症诊断荧光探针的重要补充。