Design And Synthesis Of Ru(?)/Ir(?)complexes For Photodynamic Therapy And Singlet Oxygen Detection

Cancer,as one of the high mortality diseases in the world,has seriously affected human health.Compared with traditional treatment methods including chemotherapy,radiotherapy and surgical resection,etc.,photodynamic therapy,as a high-profile platform with high spatiotemporal selectivity,low invasiveness and toxic effects,has become an emerging means of cancer treatment.During the photodynamic therapy process,photo-activated photosensitizers can transfer their excited-state energy to oxygen for producing cytotoxic singlet oxygen to cause cancer cells death.Although photodynamic therapy has many advantages,there still remain some problems to be solved.Firstly,the tumor microenvironment is hypoxic,which will seriously limit the treatment effect of oxygen-dependent photodynamic therapy.Secondly,the ideal therapeutic efficiency cannot be achieved due to the lack of targeting ability of photosensitizers.In addition,excessive production of singlet oxygen during photodynamic therapy may damage the surronding healthy cells.Therefore,it is of great signficance for tumor diagnosis and treatment to design highly efficient photosensitizers under hypoxia and singlet oxygen probes.In order to solve these issues,phosphorescent transition metal complexes have been chosed as candidates,and we designed and synthesized photosensitizers based on ruthenium(?)complexes for hypoxic photodynamic therapy and probes based on phosphorescent iridium(?)complexes for detection of singlet oxygen.And,the performance of photodynamic therapy under hypoxia and the responsiveness of the probe to singlet oxygen were studied in detail.The research content of this thesis includes the following parts:1.Design and synthesis of type I photosensitizer based on ruthenium(?)complex for photodynamic therapyTo overcome the dependency of traditional photodynamic therapy on oxygen,a series of type I photosensitizers based on ruthenium(?)complexes were designed and synthesized.Triphenylamine moiety was introduced into the ligands of Ru1,Ru3 and Ru4 to make them exhibit low oxidation potential and strong light-harvesting ability.Compared with Ru1-Ru3,Ru4 could effectively produce superoxide anions and hydroxyl radicals under hypoxia,especially under extremely low oxygen concentration.The mechanism of type I photodynamic therapy of ruthenium(?)complexes was investgated.The results showed that Ru4 could efficiently produce reactive oxygen species through type I photochemical reactions.In vitro hypoxic photodynamic therapy experiments have demonstrated that Ru4 could effectively inhibit and kill cancer cells.2.Design and synthesis of mitochondria-targeted type I photosensitizers based on ruthenium(?)bis(terpyridine)complex for photodynamic therapyAlthough type I photodynamic therapy can overcome the problem of tumor hypoxia,the therapeutic efficiency cannot be fully utilized due to the lack of targeting ability of photosensitizers.In order to improve the treatment effect under hypoxia,the mitochondria-targeted type I photosensitizer Ru(tpy-D)₂ was constructed by introducing carbazole groups on the ruthenium(?)bis(terpyridine)complex.The photosensitizer exhibited strong light-harvesting ability,which effectively produced superoxide anions and hydroxyl radicals.Ru(tpy-D)₂ exhibited excellent mitochondrial targeting ability,which could further improve photodynamic therapeutic effect.Although Ru(tpy-D)₂ could not induce the generation of singlet oxygen,sufficient ROS could be produced.Then,the phototoxicity of Ru(tpy-D)₂ was compared under both normoxia and hypoxia,which was less affected by oxygen.It is demonstrated that Ru(tpy-D)₂ achieved efficient photodynamic therapeutic effect under hypoxia.This strategy can be applied to the treatment of hypoxic tumor.3.Design and synthesis of mitochondria-targeted probes based on iridium(?)complexes for singlet oxygen detectionTwo iridium(?)complex probes(1 and 2)containing anthracene groups were designed and synthesized,which exhibited excellent selectivity and sensitivity for detection of singlet oxygen.Among them,complex 1 exhibited higher sensitivity for detection and less toxicity for cells.After incubating complex 1 with cells,we found that the complex 1 was accumulated in the mitochondria and able to capture intracellular singlet oxygen.Cellular imaging experiments were used to monitor singlet oxygen in cells,which provides an effective sensing tool for photodynamic therapy.