基于铱（III）配合物的次氯酸与pH双重靶向响应及抗菌药物筛选应用

To address the bacterial resistance from antibiotic abuse, a large number of new compounds have been synthesized for antibacteria. However, the current antibacterial methods in vivo for antibacterial drugs screening are operation multifarious and time-consuming, a simple and fast method for antibacterial drugs screening is desired. Recent study shows that bacterial infection leads to pH lower in lysosomes and a large number of hypochlorous acid generation, the lysosomal pH returns to normal when bacteria were killed. For the abnormal concentration of hypochlorous acid and pH value in infectious cells, a series of two-photon phosphorescent iridium(III) conjugated with the discriminating group of hypochlorous acid and the morpholine group are designed. The complexes will be applied to screen the antibacterial drugs in vivo by the fluorescence imaging technology. With the AND logical gate of dual-targeting-response of hypochlorous acid and pH, the complexes can be used for screening effective antibacterial drugs through the real-time fluorescence tracking of the activity and the process of antibacterial drugs. The implementation of this project will provide a new way and a new method for screening antibacterial drugs.

抗生素滥用导致了细菌产生耐药性，大量新的化合物被合成用于抗菌的研究。然而当前应用于抗菌药物活体筛选的方法操作繁杂耗时长，因此急需发展简易快速的方法应对大量化合物的筛选。研究发现细菌感染使得细胞溶酶体pH降低，同时产生大量的次氯酸，对细菌灭杀后，溶酶体pH恢复正常。针对感染细胞不正常的次氯酸浓度与pH值，本项目设计一系列整合了次氯酸识别基团与吗啉基团的双光子磷光铱（III）配合物，结合荧光成像技术，将配合物应用于对抗菌药物的活体筛选进行研究。通过对次氯酸与pH的双重靶向识别的与逻辑门（AND logical gate）响应，对抗菌药物的活性和作用过程进行实时动态荧光示踪的可视化评估，筛选出有效的抗菌药物。本项目的实施为抗菌药物的筛选提供了新途径和新方法。

细胞器，如细胞膜，溶酶体，线粒体，高尔基体，内质网和细胞核等，对细胞的正常功能起重要作用。本项目围绕着细胞器科学的发展前沿和趋势，发展了具有细胞器靶向的金属配合物和纳米颗粒，应用于细胞器的超分辨荧光成像和抗肿瘤药物研究。设计的荧光的金纳米颗粒能有效地靶向到溶酶体，并能应用于溶酶体的超分辨成像。与多肽偶联的钌金属配合物不仅仅能选择性靶向肿瘤，还能定位于肿瘤细胞内部的线粒体，在光动力作用下，能有效地杀伤肿瘤细胞和肿瘤。氟化的环金属化钌配合物能有效地同时定位与线粒体与细胞核，并能对这些细胞器进行破坏从而具有抗肿瘤效果。该项目在贵金属的细胞器靶向设计及其相关应用的顺利执行，促进了无机化学、影像学、光学与生命医药等学科的交叉发展。