Deep Red/Near-infrared Photosensitizers Based On Metallic Iridium Complexes And Small Organic Molecule: Design,Synthesis And Their Applications In Phototherapy

Phototherapy,as a new treatment method,due to high selectivity,non-invasiveness,specificity and small side effects,has been widely used in cancer treatment.The key factor of PDT is to constructe high-efficiency photosensitizer（PS）.However,the traditional organic fluorescence/phosphorescence PS faces the problem of aggregation-caused quenching（ACQ）,which leads to.Reduce the luminous efficiency and singlet oxygen（¹O₂）generation of PS in the solid state or aggregation state,limited its application in phototherapy for cancer.In 2001,Tang’s group discovered the phenomenon of Aggregation-Induced Emission（AIE）.Contrary to the ACQ phenomenon,AIE PS hardly emits light in a benign solvent,but in the solid state or in the aggregated state,the light emission is enhanced,and the ability to produce ¹O₂ is improved.However,most of the reported AIE PSs’absorption and emission wavelengths are concentrated in the short-wavelength ultraviolet or blue region,resulting in their lower tissue penetration depth and greater toxic and side effects,which is their role in biomedicine.An inherent flaw of the application.The deep red/near infrared AIE PS tissue has strong penetrating power,little damage to the organism,and can avoid the interference of the organism’s autofluorescence on the signal collection,but there are few related reports on such materials,which have the function of cancer diagnosis and treatment.The reports of similar materials are few and far between.Therefore,the purpose of this paper is to construct an efficient deep red/near infrared PS and apply it effectively in the field of phototherapy for cancer,to achieve an organic combination of photodynamic therapy and photothermal therapy,and to develop and improve an efficient photosensitizer with integrated functions of cancer diagnosis and treatment.In this paper,we designed and synthesized new phosphorescent metal iridium complexes and fluorescent small molecule nanoparticles（NPs）as deep red/near infrared phosphorescence/fluorescence PSs for phototherapy,and studied their structure-performance relationship in detail.The effective molecular construction has significantly improved its photophysical properties,¹O₂ production capacity and photothermal conversion efficiency,and successfully achieved intracellular ultrafast imaging,long-term tracking,image-guided photodynamic therapy（PDT）and photothermal therapy（PTT）.The main research contents of the paper are as follows:1.Using triphenylamine as a bridging ligand,a series of AIE metal iridium complexes and their corresponding nanoparticles with single,double,and trinuclear deep red light emission were synthesized and used in PDT as phosphorescent AIE PSs.For the first time,the structure-activity relationship between the core number of the metal center and the PDT effect is discussed.It is proposed to increase the ¹O₂ production efficiency by increasing the core number of the metal center of the complex.The ¹O₂ production capacity of PSs increases significantly with the increase in the number of metals.The increase in the number of cores increases the charge transfer from the metal to the ligand（³MLCT）,increasing its absorbance at long wavelengths.The phosphorescence quantum yield of the three-core PS3 NPs is up to 35%,the excited state lifetime is up to 4.61μs,and the molar absorption coefficient is up to 72935 m^-1cm^-1.In addition,in vivo and in vitro experiments have shown that PS3 NPs can efficiently produce ¹O₂ after irradiation and successfully inhibit the growth of cancer cells,providing a new strategy for the future acquisition of high-efficiency PS and its photodynamic therapy applications.2.By introducing electron-donating groups into the cyclic metal ligands and increasing the degree of conjugation of the auxiliary ligands,a series of deep red light emitting AIE metal iridium complexes with different core numbers and their corresponding nanoparticles were obtained.Effective control of photophysical properties and its ¹O₂ production capacity.Compared with PS with phenylpyridine as the auxiliary ligand,the electron-donating group benzothienyl prolongs the conjugation degree of PS and enhances its light absorption ability and ¹O₂ generation ability at long wavelengths,which is helpful for matching the long-wavelength excitation light source with high tissue penetration ability reducing light damage to organisms.In addition,the strategy of obtaining nanoparticles by increasing the number of metal center cores of PS and polymer encapsulating PS further improves the therapeutic effect of PS.The maximum emission wavelength of trinuclear AIE phosphorescent nanoparticle photosensitizers（S3 NPs）is 669 nm,and the phosphorescent quantum yield is 42%.Intracellular experiments show that it has good biocompatibility and excellent phototoxicity.S3 NPs can effectively inhibit the growth of tumors in mice after being irradiated with white light.The use of white light to excite metal iridium complex photosensitizers to achieve photodynamic treatment of tumors,to a large extent,reduces light damage to organisms.This work provides effective design principles for the development of high-efficiency PS suitable for long-wavelength excitation light sources for PDT.3.By introducing different numbers of metal centers into the photoactive porphyrin group,two near-infrared light emitting metal iridium complexes and nanoparticles with single and quad cores were designed and constructed as PSs realized the combined treatment effect of PDT and PTT on cancer.The introduced metal iridium center can significantly enhance the molar absorption of porphyrin at long wavelengths（650 nm）,further greatly increasing its ¹O₂generation capacity and photothermal conversion efficiency.Since the introduction of multiple metal iridium cores can significantly reduce the band gap of the PS energy band,the quad-core4-Ir NPs have excellent near-infrared absorption and near-infrared light emission,excellent ¹O₂generation capacity and light-to-heat conversion efficiency（49.48%）.In vivo and in vitro experiments have shown that 4-Ir NPs can effectively inhibit the growth of cancer cells after635 nm irradiation.The 4-Ir NPs obtained in this paper successfully overcome the traditional shortcomings of the short excitation wavelength of metal iridium complexes,and for the first time realized the application of metal iridium complexes as PS in PTT,opening up the application of metal iridium complexes in the field of cancer treatment a new platform.4.High-yield AIE red light-emitting organic fluorescent nanoparticles with D-A and D-A-D structures were prepared by simple synthesis methods,which were used as multifunctional and high-efficiency red fluorescent PS for imaging and imaging-guided PDT.The experimental results show that the two nanoparticles PS have good photophysical properties,high stability,excellent biocompatibility,and high-efficiency ¹O₂ production capacity.PS1 NPs can be used to stain cells quickly with only a slight shaking at room temperature for 5 seconds,and can achieve excellent long-term tracking ability and therapeutic effect over 14 days in vitro and in vivo.This work was the first to successfully realize a multi-function PS with ultra-fast dyeing,long-term tracking and image-guided PDT,which laid the foundation for the construction of deep red/near infrared phosphorescence AIE-PS on this basis,and provided a new strategy for design and application.