Synthesis And Application Of Near Infrared Organic Small Molecular Photothermal Agents

Cancer has become a disease of great concern because of its high incidence rate and high mortality.At present,the main treatment methods include surgery,radiotherapy,chemotherapy,etc.However,the high invasiveness and recurrence of surgical treatment,and the side effects of radiotherapy on other normal tissues and the drug resistance of chemotherapy have hindered the treatment of cancer to a certain extent.In recent years,scientists are looking for more effective treatments with fewer side effects.Photothermal therapy（PTT）is attracting more and more attention because of its non-invasive,high spatiotemporal selectivity,rapid response,and especially oxygen independence.The therapeutic effect of photothermal therapy mainly depends on the excitation light source,the photothermal conversion and the tumor targeting ability of the material.So far,many studies on photothermal therapy have been reported.Compared with materials based on inorganic materials or conjugated polymers,organic small molecules have greater advantages due to their good biocompatibility,precise structure and flexible modification.However,there are still some limitations at present.First,there are very limited types of organic small molecules that can achieve long-wavelength absorption and emission,especially in the second near-infrared window（NIR-II,1000 nm-1700 nm）;second,small molecules with multiple functions such as therapy and imaging often have complex structures and require lengthy compositing work;third,interception by the reticuloendothelial system will affect the enrichment of material in the target region.Aiming at the above key scientific issues,this thesis conducts the following research:In Chapter 1,several common biological imaging methods and tumor treatment methods are introduced,with emphasis on near-infrared fluorescence and photoacoustic imaging,and photothermal therapy.Then,several different photothermal materials are summarized,and the limitations in design and performance of current photothermal materials are discussed.Finally,for the limitations of the appeal,some feasible solutions are proposed.In Chapter 2,a molecular design strategy for constructing organic photothermal reagents via substituent engineering is proposed.By introducing trifluoromethyl groups acting as both the strong electron-withdrawing and molecular rotation motifs,an optimal compound（5）with a twisted dornor-acceptor-donor（D-A-A’）structure is faciely synthesized.The compound is further constructed into water-dispersible nanoparticles（5@FAP-NP）with tumor targeting ability by introducing folic acid group-containing polymers for nanoprecipitation.NIR-II emission（1050 nm）,high PTC efficiency（49.7%）,and remarkable PAI performance are realized upon 880 nm laser irradiation.In vivo results verify the great potential of 5@FAP-NP in tumor-targeted NIR-II FI/PAI dual-modality imaging-guided photothermal therapy to achieve realtime imaging and tumor ablation by once injection and irradiation.In Chapter 3,a small organic molecule,BDP-N₃ is designed and assembled,which has the ratiometric photoacoustic detection performance of hydrogen sulfide and the activation-type near-infrared photothermal conversion performance.By nanoprecipitation with DSPE-m PEG₂₀₀₀-FA,the spherical water dispersible nanoparticles BDP-N₃ NPs are formed.The appropriate particle size and folic acid would be beneficial to the accumulation of tumor sites for the photoacoustic detection and photothermal treatment of hydrogen sulfide（H₂S）activation in situ.H₂S will reduce the-N₃ group of BDP-N₃ NPs through the in-situ reaction to produce BDP-NH₂NPs,and produce strong absorption in the near-infrared region,which can be used for quantitative detection of hydrogen sulfide in the tumor area and near-infrared photothermal therapy of tumor tissue.Cell experiments confirm the good biocompatibility and negligible biological toxicity of the nanoparticle,as well as excellent cancer cell elimination ability after irradiation.