Design And Synthesis Of Bodipy-based Photosensitizers And The Study Of Their Antitumor Activities

Photodynamic therapy?PDT?is a new non-invasive clinical treatment for tumor in recent years.Its working principle is as follows.The photosensitizers are injected into the body and then accumulate in the tumor sites.Under irradiation with a specific wavelength of light,the photosensitizers accumulated in tumors react with oxygen?³O₂?to produce reactive oxygen species?ROS?,which oxidize and then kill the tumor cells.The systemic toxicity can be greatly reduced by tumor-targeting of the photosensitizer and local irradiation on the tumor sites.Therefore,PDT has a broad prospects of application in tumor therapy.However,the hypoxic environment of the tumor will greatly limit the effect of photodynamic therapy.Photothermal therapy?PTT?is also a new treatment for cancer.When the photothermal materials accumulate in the tumor sites,a lot of heat are released through the photothermal conversion effect under irradiation,which allow local tumor temperature to reach a certain temperature above 42oC to kill tumor cells.In addition,mild heat can induce more oxygen to enter the tumor tissue.Therefore,PTT can promote the effect of PDT when they are combined.Boron dipyrromethene?BODIPY?photosensitizers have high molar extinction coefficient,which can result in high singlet oxygen yield or high photothermal conversion efficiency by structural modification.Therefore,they attract increasing attention in the field of PDT and PTT in recent years.In this paper,BODIPY dimer Di-BDP and trimer Tri-BDP were designed and synthesized,and they were encapsulated by the amphiphilic polymer PEG₁₁₄-PCL₆₀ to prepare the corresponding nano-sized photosensitizers.Their photo-physicochemical properties,photodynamic and photothermal effects of Di-BDP-M,Tri-BDP-M,Tri-BDP-F and Tri-BDP-F were investigated.Their photodynamic and photothermal effects were also investigated at the cellular and animal levels.In addition,an active targeting photosensitizer cRGD-BDP was designed and its synthetic route was explored.In this paper,the specific contents are summarized as follows:Chapter 1 introduces the present treatment of tumor,the principle and application of PDT and PTT,the development and application of nano-sized drugs.Chapter 2 reports the synthesis of BODIPY dimer Di-BDP and trimer Tri-BDP.Then,they were encapsulated by the amphiphilic polymer PEG₁₁₄-PCL₆₀ to prepare the corresponding nano-sized photosensitizers with good biocompatibility,suitable particle size and excellent EPR effect.Compared with the free drugs Di-BDP-F and Tri-BDP-F,the nano-sized photosensitizers Di-BDP-M and Tri-BDP-M showed higher stability,better photothermal effect or singlet oxygen production efficiency.Cellular experiments showed that nano-sized photosensitizers had higher cell uptake times.They were mainly internalized via clathrin-mediated endocytosis and then located in the lysosome.DHE and AO staining experiments demonstrated that nano-sized photosensitizers induced intracellular production of singlet oxygen and lysosomal disruption.Cytotoxicity experiments showed that nano-sized photosensitizers killed tumor cells by a synergistic PDT/PTT effects.The animal experiments showed that nano-sized photosensitizers exhibited better tumor accumulation due to their long-circulation and EPR effect.Tissue ROS experiments showed that nano-sized photosensitizers produced singlet oxygen under irradiation.Infrared thermography revealed nano-sized photosensitizers generated the potent hyperthermia in the tumor site under irradiation.Anticancer efficacy revealed Di-BDP-M and Tri-BDP-M triggered the tumor ablation.H&E staining experiments revealed nano-sized photosensitizers could induce tumor damage.In Chapter 3 acylate-glycine-aspartate cycled tripeptide?cRGD?was introduced into the BODIPY core to synthesize an active targeting photosensitizer cRGD-BDP via Click reaction.At the end of this thesis,the ¹H and ¹³C NMR spectra of some of compounds are listed in the Appendix.