可用于肿瘤乏氧检测与治疗的荧光/磷光共轭聚电解质的设计、制备及其生物应用

Hypoxia, one of the most important features of many diseases including cancers, has been found in more than 90 % of solid tumors. Hence, accurate monitoring of oxygen level in solid tumors is of paramount important for early diagnosis and therapy. The phosphorescence of transition-metal complexes can be quenched by oxygen through the energy transfer from the long-lived triplet excited state of complexes to the triplet ground state of molecular oxygen. Based on this mechanism, luminescent imaging of hypoxia in tumor cells has been an important method to monitor oxygen level. However, there are still several key problems which need to be solved. For example, the water-solubility of complexes is usually poor. Moreover, the change of phosphorescence intensity can be easily interfered by external environment (such as background autofluorescence) and most hypoxia imaging was conducted at cell level. To solve these problems, in this project, we put forward a new strategy to realize fluorescent/phosphorescent conjugated polyelectrolyte by introducing oxygen-sensitive phosphorescent complexes into fluorescent conjugated polyelectrolyte, which will endow the oxygen probe with good water-solubility. Simultaneously, a ratiometric oxygen probe can be realized to monitor oxygen concentration quantitatively by using the oxygen-insensitive fluorescent signal as reference. Besides, the use of time-resolved luminescent imaging technology can eliminate the interference of autofluorescence and improve the signal to noise ratio significantly. Furthermore, the oxygen probes suitable for small-animal hypoxia imaging will be developed, and transition-metal complexes will be also served as highly efficient photosensitizers to achieve both tumor hypoxia detection and photodynamic therapy.

乏氧是肿瘤等疾病发生的最重要特征之一，90%以上的实体肿瘤中均有乏氧细胞存在。准确测定肿瘤乏氧状态对其早期诊断和治疗具有重要意义。利用磷光金属配合物三线态激发态与氧气三线态基态之间能量转移导致的磷光发光变化，通过荧光成像技术实现肿瘤细胞乏氧成像，成为重要的乏氧检测方法。目前这一领域存在许多关键问题需要解决，如配合物水溶性差、磷光强度变化易受外界环境（如背景荧光）干扰、乏氧检测大都在细胞层次等。因此，在本课题中我们提出将氧敏感的磷光金属配合物引入到荧光共轭聚电解质中来制备荧光/磷光共轭聚电解质，既可解决探针的亲水性问题，同时引入参比荧光信号实现对乏氧的比率法检测，可定量检测氧分压；利用磷光与背景荧光发光寿命的不同，通过时间分辨荧光成像有效消除背景荧光干扰，提高检测的信噪比和灵敏度；进一步发展可适用于小动物乏氧成像的探针，利用过渡金属配合物作为高效光敏剂，同时实现肿瘤的乏氧检测与光动力学治疗。

乏氧是肿瘤等疾病发生的最重要特征之一，准确测定肿瘤乏氧状态对其早期诊断和治疗具有重要意义。利用磷光金属配合物三线态激发态与氧气三线态基态之间能量转移导致的磷光发光变化，通过光学成像技术实现肿瘤细胞乏氧成像，成为重要的乏氧检测方法。针对这一领域存在的诸多问题，如配合物水溶性差、磷光强度变化易受外界环境干扰、乏氧检测大都在细胞层次等，在本项目中，我们围绕“可用于肿瘤乏氧检测与治疗的荧光/磷光共轭聚电解质的设计、制备及其生物应用”开展了系统研究。首先将氧敏感的磷光金属配合物引入到共轭聚电解质中，设计、制备了多类型可用于肿瘤乏氧检测与治疗的荧光/磷光共轭聚电解质，既解决了探针的水溶性问题，同时引入参比荧光信号实现对乏氧的比率法检测，可定量检测氧分压；利用磷光与背景荧光发光寿命的不同，通过时间分辨光学成像有效消除了背景荧光干扰，显著提高了检测的信噪比和灵敏度；进一步发展了可适用于小动物乏氧成像的探针。另外，我们利用过渡金属配合物作为高效光敏剂，同时实现了对肿瘤的乏氧检测与光动力学治疗。这些研究结果为今后开发面向实际生物医学应用的新型肿瘤诊断和治疗一体化平台打下了坚实基础。在本项目的支持下，到目前为止，已在Chemical Reviews、Journal of the American Chemical Society、Angewandte Chemie International Edition、Advanced Functional Materials、Chemical Communications、ACS Applied Materials & Interfaces等在内的国际著名学术期刊发表SCI论文35篇。研究工作多次被Wiley出版社的MaterialsViews、MaterialsViewsChina和ChemistryViews网站进行专题推荐介绍。在Chemical Reviews (2018, 118, 4) 发表综述文章，系统总结了用于时间分辨生物检测与成像领域的研究进展。获授权中国发明专利4件，另有10件中国发明专利已经公开。在本项目执行期内，项目负责人入选江苏省“333高层次人才培养工程”中青年科学技术带头人，作为第三完成人获得2018年度国家自然科学奖二等奖等科技奖励，培养了博士、硕士研究生二十余名。本项目经费使用合理。

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