Synthesis Of Near Infrared Triggered D-A-A Photosensitizers And Their Application In Tumor Therapy

Malignant tumors with the characteristics of rapid abnormal growth,invasion toward normal tissues exhibit strong threat to human health.Photodynamic therapy（PDT）has been gradually applied to tumor treatment because of its noninvasive,lesion-selective,and irradiation-localized nature,which thereafter reduced of side effects.PDT mainly relies on photosensitizer to produce cytotoxic reactive oxygen species to kill cancer cells under the irradiation of a specific light source.In view of the stronger tissue penetration depth of near-infrared light,the near-infrared light based photosensitizer shows the great advantages in PDT.However,it is difficult to achieve a satisfactory prognosis with a single PDT strategy,due to the physiologic complexity of malignant tumors and the local characteristics of PDT.Herein,two D-A-A photosensitizers that can be activated by near-infrared light were prepared and introduced for PDT of tumor.Further,photothermal therapy and chemotherapy were combined respectively with PDT to evaluate the efficacy of combinational treatment strategy and explore its application in the elimination of solid tumors.In chapter 1,the characteristics of tumors and their harm to human body were briefly described,and the current strategies for tumor treatment and their advantages and disadvantages were introduced,mainly including the mechanism of PDT,its unique advantages and disadvantages in tumor treatment;a variety of new materials used in photothermal therapy and the application in tumor treatment at present were reviewed.Chemotherapeutic drugs and their problems in the clinical application were introduced;The breakthrough of combined therapy in the tumor treatment was emphasized.In chapter 2,a type of D-A-A small molecule ABTM was designed and synthesized based on donor-receptor structure,and it was prepared into nanoparticles by the nanoprecipitation method.ABTM nanoparticles could produce cytotoxic ROS under 660 nm near-infrared light,which has been successfully verified in aqueous solution and cell level.The hypoxia tumor microenvironment limited the efficacy of PDT.Ti₃C₂ MXene,a two-dimensional layered material with excellent high photothermal performance,large specific surface area,and good biosafety,was selected as the photothermal agent to combine photodynamic therapy,so as to explore the effect of combined therapy.The type of D-A-A photosensitizer ABTM was loaded onto Ti₃C₂ to prepare the composite nano materials by the nanoprecipitation method.The production of ROS by Ti₃C₂-ABTM was successfully verified at the cellular level,and the cytotoxic ROS could kill tumor cells.The photothermal properties of Ti₃C₂ and Ti₃C₂-ABTM under 808 nm near-infrared light were investigated.Meanwhile,ROS and heat generated under 660 nm and 808 nm laser irradiation were combined to treat tumor cells to explore the anti-tumor effect of the combined strategy in vitro.In Chapter 3,based on the skeleton structure of D-A-A type small molecule in Chapter 2,we successfully synthesized D-A-A type small molecule CBTM that generated reactive oxygen species under 660 nm near-infrared light.In order to improve the tumor inhibition effect,CBTM-YSV composite nanoparticles were formed by hydrogen bonding andπ-πstacking with a tyrosine-serine-valine（YSV）tripeptide,which can inhibit the growth of tumor cells.The effect of PDT and chemotherapy on solid tumor was investigated.The ability of CBTM nanoparticles to produce reactive oxygen species in solution was verified,the ability of CBTM and CBTM-YSV to produce reactive oxygen species was verified at the cell level.Cytotoxicity showed that the combined tumor killing effect was less than 20%,which was further demonstrated by cell viability staining.Balb/c mice were used as research objects to establish a subcutaneous tumor model,and the combined treatment of PDT and chemotherapy had an inhibitory effect of 67%on solid tumors.The experimental results showed that the composite nanoparticles exhibit a good inhibitory effect on tumor cells and solid tumors in vitro and in vivo.