多功能诊疗磷光金属配合物的设计及抗肿瘤机制研究

The investigation of cellular and in vivo distribution and real-time in situ monitoring of therapeutic efficacy of anticancer drugs is becoming a very active topic in the field of anticancer research. Phosphorescent metal complexes have unique anticancer properties and excellent photochemical and photophysical properties, such as environment-sensitive emission, significant Stokes shifts, visible-light/near-infrad two-photon excitation phosphorescence, and relatively long emission lifetimes, and they are ideal candidates to build theranostic platforms. Based on our previous work, this project will design and synthesize multifunctional phosphorescent metal complexes as theranostic anticancer agents that combine anticancer activities with phosphorescent imaging capabilities. We will determine their intracellular uptake levels and subcellular localizations. The anticancer mechanisms will be studied in detail, which include the inhibitory activities and structure-activity relationships, the modes of cell death, the regulation of cell signaling pathways and the molecular targets. The in vivo antitumor activities, imaging properties and theranostic potential will also be investigated. The goal of the project is to indentify phosphorescent metal complexes with tumor-targeting properties, organelle- or molecular-targeting capabilities, high antitumor activities and excellent imaging performance, as well as the capability to monitor the changes in cell organelles or the expression level of biomolecules in real-time mode. The research of the project will contribute to the discovery of unknown biological phenomena, and will also lay the experimental and theoretical foundation for the development of novel metal-based anticancer agents.

抗肿瘤药物在细胞内和体内的分布以及药物效果的实时原位监测是国内外抗肿瘤领域十分活跃的研究课题。磷光金属配合物具有独特的抗肿瘤性质和优异的光学特性，如环境敏感的磷光发射，大斯托克斯位移，可见光/双光子近红外光激发，和长磷光寿命等，是构建新型的诊疗一体化药物的理想平台。在上一个基金工作基础上，本项目拟设计合成具有靶向抗肿瘤活性及磷光成像能力的多功能诊疗一体化金属配合物；测定它们的摄取水平和亚细胞器定位；研究其抗肿瘤机制，包括对肿瘤细胞的生长抑制活性和构效关系、细胞死亡方式、对细胞信号通路的调节和分子靶点；研究其体内抗肿瘤活性、体内成像性质；探索其作为诊疗一体化药物的潜能。目标是发现兼具肿瘤靶向、细胞器或分子靶向、高抗肿瘤活性和优异成像性能的磷光金属配合物，对配合物诱导的细胞生理变化过程中细胞器或生物分子表达量的动态变化实时示踪，揭示未知的生命现象，为发展新型的金属基诊疗药物提供实验和理论基础。

抗肿瘤药物在细胞内和体内的分布以及药物效果的实时原位监测是国内外十分活跃的研究课题。磷光金属配合物具有独特的抗肿瘤性质和优异的光学特性，如环境敏感的磷光发射，大斯托克斯位移，可见光/双光子近红外光激发和长磷光寿命等。同时，这些配合物也具有非常丰富的抗肿瘤性质。本项目设计合成了具有分子靶向、亚细胞器靶向、抗肿瘤活性及磷光成像能力的多功能诊疗一体化金属配合物。首先，利用其磷光性质，我们测定它们的摄取水平和亚细胞器定位。采用了多种研究手段，我们研究了其抗肿瘤机制，包括对肿瘤细胞的生长抑制活性和构效关系、细胞死亡方式、对细胞信号通路的调节和可能作用的分子靶点。此外，我们还研究了它们的体内抗肿瘤活性、体内成像性质。通过这些研究，我们展示了这些分子作为诊疗一体化药物的潜能。经过系列的研究，我们发现几十个兼具肿瘤靶向、细胞器或分子靶向、高抗肿瘤活性和优异成像性能的磷光金属配合物。我们对配合物诱导的细胞生理变化过程中细胞器或生物分子表达量的动态变化实时示踪。项目共发表标注项目的论文21篇，其中包括国际化学知名刊物Adv. Sci.（2篇）、Chem. Sci. （3篇）、ACS Appl. Mater. Interfaces（4篇）、J. Med. Chem. (1篇)、Chem. Commun. (1篇)、Chem. Eur. J. (4篇)和Nanoscale（2篇）等。项目负责人多次参加国内外学术会议并做报告。项目培养了博士研究生4名和硕士研究生3名。总之，项目的完成情况良好。