基于环金属Ir(III)配合物的线粒体双光子荧光探针研究

The traditional model of mitochondria as static, bean-shaped organelles are known in the past fifty years. However, recent studies lead to renewed appreciation for the fact that the mitochondria are motile and highly dynamic organelles. The dynamic changes of mitochondria include biogenesis, selective degradation, shape changes involving fission and fusion from a reticular-like mitochondrial cellular network, and rapid transport along the cell body to extremities. These dynamic processes are essential for mammalian development, and are involved in vital processes such as cellular differentiation, cell cycle, cell growth, and even cell death. Several evidence suggest that dysfunctions of mitochondrial dynamics are engaged in several diseases, such as Parkinson’s disease, Alzheimer’s disease, neurodegeneration, multiple sclerosis and cancer. Although the concept that bolstering mitochondrial health and/or replacing dysfunctional and potentially toxic mitochondria with functional mitochondria to confer diseases is attracted, the current state of knowledge related to mitochondria as a dynamic organelle is nascent. In addition, tools are currently too limited to satisfactorily track the dynamics. Fluorescence microscopy has been utilized in various studies to offer a novel approach for visualizing mitochondrial morphological details. However, commercial organic probes are not suitable for tracking mitochondrial morphological dynamics due to their poor photostabilities that are unable to meet the large time frame of life processes. In addition, these dyes may also cause extensive cellular damage and unwanted background signals due to the ultraviolet radiation required for their excitation and small Stokes shifts. These short excitation wavelengths also inhibit the application of these materials in thick tissues or live animals due to the resultant short penetration depth. Different from organic molecule, iridium(III) complexes have been attracted to apply as mitochondrial probes due to their excellent photo-physical properties. The key point of this project is to develop novel iridium(III) complexes as two-photon wash-free phosphorescent trackers to monitor mitochondrial dynamics. We hope that the structure-activity relationship can be obtain from this project and these findings may aid in the design and development of mitochondrial dynamics trackers.

线粒体科学是当今化学、生命科学及分子医学最为活跃的交叉研究领域之一，针对线粒体的深入研究，对衰老相关疾病、代谢性疾病、肿瘤等的控制和治疗具有重要意义。目前关于线粒体形态动态变化的研究仍很少，特别是线粒体形态及其与线粒体的代谢行为、线粒体功能和相关疾病的关系仍是具有挑战性的国际难题。本项目针对实现线粒体形态的实时、原位的灵敏检测这一关键问题开展研究，主要研究内容和目标是构筑基于金属Ir(III)配合物的双光子、免分离线粒体形态示踪探针，获得发光效率高、光稳定性高、发光寿命长的探针，克服现有有机小分子探针光稳定性差、成像时间短、无法应用于动物活体等缺点，实现对线粒体形态动态变化的实时检测及长时间跟踪，初步探索探针结构与性能之间的关系，提炼出具有一定普适的结构-性能规律，为线粒体示踪探针的理性设计奠定基础。

线粒体科学是当今化学、生命科学及分子医学最为活跃的交叉前沿研究领域之一，开展线粒体的相关基础研究是重要的前沿科学问题，与若干重要疾病的诊疗密切相关。本课题按照研究计划进行，重点围绕金属铱配合物线粒体探针的靶向控制因素、双光子荧光探针的设计以及线粒体形态示踪等方面开展工作。成功构筑金属铱配合物小分子库，配合物结构数目超过200种，且还在持续增加中。从中筛选获得一批具有线粒体靶向荧光成像探针，通过配体调节油水分布系数、电荷数等因素，总结金属铱配合物的线粒体靶向性控制因素，归纳实现金属铱配合物线粒体靶向性的普适性规律，为线粒体荧光探针的设计提供了理论基础。初步探索了金属铱配合物结构与其双光子性质之间的构效关系，获得一例具有优异双光子性质的线粒体靶向金属铱配合物。以所获得的线粒体靶向探针为基础，在活体细胞、组织、模式动物等不同层次上，对线粒体的形态、代谢等动态行为进行示踪观察。在国际重要刊物上发表SCI论文4篇，圆满完成了课题的预期目标。另有待发表论文2篇，待申请中国发明专利1件。项目投入经费26.0万，支出25.0393万，各项支出基本与预算相符。剩余经费0.9607万，剩余经费计划用于本项目研究后续支出。