Design,Synthesis And Application Of Novel Organic Small Molecular Photosensitizers For Photodynamic Therapy

Photodynamic therapy(PDT)as an important kind of tumor therapy technique has attracted widespread attention due to its non-invasive and controllable characteristics,and low side effects.The core of the PDT treatment process is the photosensitizers,and their performance determines the PDT effect.The current problems include:(1)The selectivity of photosensitizers is low,and cannot locate in the target tumor tissue.In addition,the reactive oxygen species(ROS)life is extremely short,resulting in a limited scope of effective PDT.(2)The intrinsic hypoxic microenvironment of tumors greatly reduces the generation efficiency of reactive oxygen species.(3)The excitation light source is mostly visible light with a short wavelength,and the penetration depth of the tissue is limited.(4)In addition,the imaging effect of many photosensitizers on tumor sites is severely affected by aggregation-caused quenching(ACQ)effect,and their imaging resolution is greatly reduced.To solve the above problems,we have successfully designed and synthesized two porphyrin molecules that can specifically target lysosomes and mitochondria in the subcellular structure of cancer cells,as well as iridium(III)complexes with aggregation-induced phosphorescent emission(AIPE)properties for hypoxic imaging and photodynamic therapy.The content of the thesis includes the following parts:1.Design and synthesis of organelle-targeted photosensitizers based on porphyrin derivatives for photodynamic therapyWe have designed and synthesized two porphyrin derivatives that specifically target lysosomes and mitochondria in the subcellular structures of cancer cells.Colocalization experiments and Pearson correlation coefficients demonstrated that they can efficiently aggregate in lysosomes and mitochondria,respectively.In addition,they were applied for cell imaging experiments with different types of cancer cells,and the results showed that both porphyrin derivatives could be uptaken by different cancer cells.An evaluation of the PDT effect was subsequently carried out.Compared to PDT in the cytoplasm,reactive oxygen species produced in lysosomes and mitochondria can rapidly destroy their structures and functions,such as changing lysosomal membrane permeability,releasing various proteases and hydrolases to disrupt intracellular environmental balance and reducing mitochondrial membranes potential.In turn,the cancer cells are killed and the photodynamic treatment effect is greatly improved.2.Design and synthesis of photostable AIPE-active iridium(III)complex for hypoxia bioimaging and photodynamic therapyWe have designed and synthesized a phosphorescent iridium(III)complex(Ir-AIPE-S)with the property of aggregation-induced phosphorescent emission.The AIPE could well solve the problem that the photosensitizer is easily aggregated in imaging to cause quenching and poor photostability.By combining laser confocal microscopy with time-resolved luminescence microscopy,complex Ir-AIPE-S can be used for tumor hypoxia imaging due to its excellent photophysical properties,such as high photostability,good biocompatibility,long phosphorescence lifetime and high quantum efficiency.In addition,the phosphorescent iridium(III)complex also exhibited a good singlet oxygen generation ability to achieve photodynamic therapy in both normoxia and hypoxic conditions.