Synthesis Of Photosensitizers With Near-infrared Absorption Or Aggregation-induced Phosphorescence Enhancement For Photodynamic Therapy

Photodynamic therapy（PDT）is a new anticancer therapeutic method that uses photosensitizer to produce singlet oxygen or other types of reactive oxygen species to kill cancer cells.It has the advantages of good spatiotemporal accuracy,low toxicity and non-invasive,which has aroused extensive research interest.The core of the whole process is photosensitizer,whose performance determines the therapeutic effect of PDT.However,there are some problems of traditional photosensitizers:（1）excitation of these photosensitizers usually needs short-wavelength visible light,which shows weak tissue penetration ability to reduces PDT effect;（2）Most of the organic photosensitizers exhibit poor water-solubility,resulting in molecule aggregation in physiological environment to quench the excited states,which decreases the generation of reactive oxygen species to reduce PDT effect.To address the above two problems,we designed and synthesized the pyrrolidone derivatives and iridium（III）complexes as PDT photosensitizers,which exhibited near-infrared（NIR）absorption and aggregation-induced phosphorescence enhancement（AIPE）,respectively.The main contents of this thesis include the following two parts:1.Design,synthesis and application of near infrared photosensitizer based on pyrrolidone derivatives in photodynamic therapyThe NIR light excitable photosensitizers have deep tissue penetration depth to achieve non-invasive PDT in deep subcutaneous tissues,which is of great significance for practical applications of PDT in clinical medicine.Pyrrolidone derivatives possess the advantages of high fluorescence quantum yield,good photostability and adjustable absorption wavelength,which can be utilized to develop NIR light excitable PDT photosensitizers for the treatment of tumors located in deep tissues.In this part of the work,we designed two kinds of near-infrared photosensitizers based on pyrrolidone derivatives:BBB-NO₂ with D-A-D structure and BBB-NH₂ with A-D-A structure（D:Donor）;A:Acceptor（Acceptor）,which exhibit strong absorption in the near-infrared light band.Upon excitation of NIR light,both of the compounds could generate high cytotoxic singlet oxygen.In order to improve the water-solubility and biocompatibility,the above two compounds were coated with amphiphilic polymer DSPE-m PEG₅₀₀₀ to obtain nano particles,BBB-NH₂ NPs and BBB-NO₂ NPs,respectively.Under the irradiation of NIR light,the nanoparticles showed good ability to produce singlet oxygen and photothermal effect.The therapeutic effect of the nanoparticles was evaluated through cell apoptosis experimetns,which indicated that the structures and physiological functions of cancer cells were destroyed during the PDT process,leading to cell apoptosis,demonstrating high-efficiency therapeutic effect on cancer cells.2.Application of iridium（III）complexes with aggregation induced phosphorescence enhancement in photodynamic therapyAggregation-induced phosphorescence enhancement is that the phosphorescence intensity is significantly higher in aggregation or solid state than in solution.The mechanism is mainly attributed to the inhibition of the torsion of each group around the single bond.This material can effectively solve the problem that the poor water solubility of organic photosensitizer in biological system leads to molecular aggregation,which leads to excited state quenching,resulting in the weakening of PDT effect.The iridium（III）complexes possess the advantages of long-lived triplet excited states,high efficient singlet oxygen quantum yield and adjustable excitation wavelength,which could be served as excellent PDT photosensitizers.According to structural modification,the iridium（III）complex could be endowed with AIPE effect,which can effectively solve the disadvantage of PDT effect weakening caused by aggregation quenching in biological system.The ROS detection,cell apoptosis experiments,etc.,demonstrated that the iridium（III）complexes with AIPE effect exhibited good ability to produce singlet oxygen,improving the PDT effect in biological environments.