Design,Synthesis And Application Of Atomic Iodine/Tetrastyrene Group Substituted Aza-BODIPY

In the past 100 years,cancer has become one of most lethal killers,which has seriously affected the quality of human life.At present,there are conventional and mature methods for the treatment of cancer,such as surgery,radiotherapy,chemotherapy,etc.,but these treatment methods have great wounds,strong toxic and side effects,and poor targeting.Therefore,it is particularly urgent to develop more universal tumor treatment methods.Phototherapy,including photodynamic therapy(PDT)and photothermal therapy(PTT),is a new technology for the treatment of tumors.Compared with the traditional treatment methods,phototherapy has the advantages of less invasion,low toxicity,the controllability of time and space,which has aroused extensive research interest of scientists.In photodynamic therapy,reactive oxygen species(ROS)are the main mediators of the destruction of cancer cells.Oxygen,photoluminescence and photosensitizers(PS)are necessary for ROS production.Photosensitizers absorb the light energy of the excited light and reach the excited state,and then transfer the energy to oxygen through energy transfer or electron transfer to form cytotoxic ROS.For photothermal therapy,light energy is converted into heat energy by photothermal agents,leading to thermal ablation of cancer cells,and then cell death.For single photodynamic therapy,because of the poor penetration depth of the tissue of the excitation light source and the low oxygen content in the tumor,the photodynamic effect is severely limited.However,single photothermal therapy can stimulate the cells to produce heat suppressor proteins,so that some tumor cells will remain in the tumor site after photothermal therapy,which may lead to cancer recurrence.But if the two treatment methods are combined,the heat generated by the photothermal therapy can promote blood flow and increase the oxygen content of tumor site,thus improving the photodynamic effect.Photodynamic therapy can also effectively kill the cells with heat inhibition effect,which are complementary effectively.Therefore,synergistic phototherapy will be an effective strategy for tumor treatment.In this study,aza-BODIPY dyes were selected as the research object,and a series of near-infrared phototherapy agents with excellent effects were designed and synthesized.The main research contents of this paper are as follows:1.Design and synthesis of aza-BODIPY based on heavy atom effect and its applications in photodynamic and photothermal synergistic therapyIn photodynamic therapy,the low efficiency of intersystem crossing limits the production of singlet oxygen and the application of aza-BODIPY in PDT.The effect of heavy atoms can improve the intersystem crossing and enhance the effect of photodynamic therapy.Besides,heavy atoms can effectively quench the luminescence of aza-BODIPY and improve the photothermal effect.In this chapter,eight aza-BODIPY derivatives with different numbers and positions of iodine atoms were designed and synthesized,and their structures were characterized in detail.After comparing its photodynamic and photothermal effects,B6 with the nice photothermal and photodynamic effects was selected as the object of further study.The problem of poor water solubility of B6 was solved by coating with DSPE-mPEG₅₀₀₀,and the obtained B-6I NPs showed good water solubility and biological compatibility.B-6I NPs can also produce active oxygen and heat well when irradiated by laser in aqueous solution,indicating that the nanoparticles also have good photodynamic and photothermal effects.The cell experiments showed that B-6I NPs also had good photodynamic and photothermal effects in the cell,and could effectively inhibit the growth of tumor and kill the tumor cells.Therefore,the introduction of heavy atoms in phototherapy agents can effectively enhance the effect of photothermal and photodynamic treatment,which provides a new way for the design of synergistic phototherapy agents in the future.2.Design,synthesis and exploration of photothermal properties of Aza-Bodipy substituted by tetrastyrene groupsIn photothermal therapy,reducing the fluorescence quantum efficiency of photothermal agents can effectively reduce the radiation transition and thus enhance the photothermal effect.In other words,the fluorescence intensity of photothermal agents is closely related to its photothermal effect.In order to explore the relationship between the change of fluorescence intensity and the photothermal effect under the combined action of molecular rotation twist and fluorescence quenching,we designed and synthesized two Aza-Bodipy(A1,A2)containing tetrastyrene groups,and two compounds A3 and A4 without tetrastyrene groups as reference.The methoxy group was introduced to enhance the photothermal effect of Aza-Bodipy skeleton.The maximum absorption and emission peaks of Aza-Bodipy synthesized in this chapter are located in the near-infrared region.The introduction of tetrastyrene groups cause the maximum emission peak of A1(A2)to be redshifted compared with the corresponding A3(A4)and the photothermal effect of A2 is also significantly enhanced compared with the reference compound.The fluorescence intensity of A2 in different ratios of water(H₂O)and tetrahydrofuran(THF)was firstly decreased,then increased and then decreased due to the combined action of rotation distortion and fluorescence quenching of tetrastyrene groups.In this process,the photothermal effect of A2 is not only related to its fluorescence intensity,but also an important influencing factor of light absorption intensity.The combined action of the two factors has a dynamic influence on the photothermal effect of Aza-Bodipy.A2,which has the best photothermal effect,was selected to conduct the experiment of living and dead cells.A2 can kill Hela cells well.It can be seen that the introduction of groups with intramolecular rotation properties in phototherapy agents can regulate the photothermal effects,which provides a new idea for the design and biological application of photothermal agents in the future.