Study On Antitumor Activity Of Ruthenium And Iridium Complexes As Photosensitizers And Long-circulating Liposomes

At present,cancer has become the most difficult problem for medical workers over the world.Among them,the high mortality and recurrence rate of cancer make it difficult to be solved.Since the 21st century,with the increasing innovation of science and technology,the current treatment methods mainly include chemotherapy,surgical resection and radiation therapy.Based on the consideration of many factors,chemotherapy has become a treatment option considered by more and more patients.Among many chemotherapeutic drugs,cisplatin has been widely used clinically.However,the shortcomings of cisplatin itself have severely limited its clinical application.Therefore,finding a low-toxicity,targeted,and specific metal complex antitumor drug needs to be solved at present.Metals ruthenium?II?and iridium?III?,as transition metals of the same main group of platinum,have attracted more and more attention.In this thesis,a series of ruthenium?II?complexes and two series of iridium?III?complexes were synthesized.The structures of the synthesized complexes were characterized by ESI-MS,ultraviolet infrared,fluorescence,particle size potentiometer,TEM,¹H NMR and ¹³C NMR,and their antitumor activity and mechanism were further studied.In this dissertation,the antitumor activity and mechanism of the synthesized complexes were explored in vitro and in vivo,respectively.First,the in vitro toxicity test was performed by using MTT colorimetry.The results showed that these complexes had no inhibitory effect on cell growth.However,when using illumination or using lecithin and functionalized phospholipids to prepare functionalized long circulating liposomes,the complex has good cytotoxicity toward tumor cells.Further experiments such as AO/EB,DAPI staining,and subcellular localization confirmed that the complexes could enter the cell and cause apoptosis.Through single-cell gel electrophoresis experiments,we found that the complexes can cause intracellular DNA damage,and its fragmentation can further block the cell cycle and induce apoptosis.Flow cytometry can accurately and quantitatively analyze the degree of tumor cell apoptosis.Reactive oxygen species?ROS?levels,calcium ion concentration,mitochondrial membrane potential,cytochrome c,and autophagy were analyzed by high content imaging analysis system and flow cytometry.The experimental results show that the complexes can lead to an increase of intracellular ROS and Ca²⁺levels,a decrease of mitochondrial membrane potential,further promote to release of cytochrome c.In addition,complexes can also induce apoptosis by causing cell autophagy.Finally,the apoptotic pathway related proteins were investigated by Western blot experiments.The above results indicate that the complexes induce apoptosis and inhibit cell growth and reproduction in various ways.Additionally,we also selected several complexes with high cytotoxic activity to perform antitumor activity studies in vivo.First,a xenograft tumor model?CDX?of tumor cells was established in nude mice,in which the mice were randomly divided into the administration group and the control group,and then the tissue morphological changes of nude mice were observed by H&E staining method.The experimental results also show that the complexes exert high antitumor activity in vivo.In summary,the new complex designed and synthesized has an ideal antitumor activity in vivo and in vitro.