Synthesis And Properties Of Selectively Antimicrobial And Anticancer Photosensitizers With Aggregation-induced Emission Characteristics

Cancer and pathogen infection have been threatening the health of the human being.Traditional treatment methods demonstrate a lot of disadvantages such as invasiveness,obvious side effects,and difficulties in eliminating hidden lesions.In particular,the emergence of drug resistance makes anti-cancer and anti-bacterial are encountering great serious crisis.As an emerging and non-invasive treatment method photodynamic therapy（PDT）utilizes photosensitizer（PS）,light and endogenous oxygen to kill cancer cells or pathogens which shows a lot of advantages including non-invasiveness,minimal side effects,elimination of the hidden lesions and limited drug resistance compared with traditional treatment methods.PS plays a crucial role in PDT.Traditional photosensitizers encounter low reactive oxygen species generation efficiency due to the aggregation induced quenching（ACQ）effect and the nonradiative pathways causing by π-π interation.On the contrary,PSs with aggregation-induced emission（AIE）properities can reduce the radiative decay and the energy gap of the intersystem crossing which can improve the efficient of ROS productionand therefore show great potential in photodynamic anticancer and antimicrobial.Although,PS with AIE properties has solved the problem of low ROS genenation effiency encountered in traditional PS and achieved satisfactory results in anticancer and antimicrobial PDT treatment,there are still great challenges in selective photodynamic therapy bacteria and cancer cells.Some PSs can selectively interact with one target by modifying with specific targeting groups.Nevertheless,most of these PS only have one single target which is hard to treat multiple targets,separately.Therefore,in this thesis,we hope to design and synthesize PSs with AIE properties for time-regulated selective photodynamic antibacterial and anticancer studies.The details were described as follow:1.Synthesis and optical properties of dithiophene acrylonitrile-based aggregation-induced emission photosensitizers:Seriesof lipophilic cationic AIE PSs with D-π-A structure were synthesized through construction of push-pull electron system using dithiophene acrylonitrile as fluorescence framework.The structures of these PSs were characterized by ¹H NMR,¹³C NMR and high resolution mass spectrometry.The optical properties of these PSs were studied by UV-Vis spectrophotometer and fluorescence spectrometer.The results showed that when triphenylamine were modified with methoxy group,the maximum excition and emission wavelength were red-shifted;while the fluorescence quantum yield decreased;its AIE performance,reactive oxygen generation ability and ¹O₂ efficiency were significantly decreased.The extension of alkyl chain on the electron-withdrawing pyridine salt had no significant change for the absorption and emission wavelength and fluorescence quantum yield,while the production capacity of reactive oxygen species and the efficiency of ¹O₂ gradually decreased.Among them,TM-PF6demonstrated the best performance in ROS and singlet ¹O₂ generation.2.From cell membrane to mitochondria:selective photodynamic antibacterial/anticancer thearpy with dithiophene acrylonitrile-based aggregation-induced emission photosensitizers:The photodynamic antibacterial and anticancer properties of TM-PF6 were investigated by plate counting method and MTT assay.TM-PF6 could be effectively used for photodynamic ablation of Gram-positive and Gram-negative bacteria after incubation with bacteria for 10 min and white light irradiation for 30 min.,while it hardly had any phototoxicity for both cancer cells and normal cells under the same conditions.These indicated that TM-PF6 could selectively photodynamic antibiosis.When the incubation time was extended to 3 h,TM-PF6 could effectively kill cancer cells,while it kept no phototoxicity to normal cells.Fluorescence imaging,Western blot analysis and RNA transcriptome analysis were used to investigate the mechanism of TM-PF6’s selective for antimicrobial and anti-tumor activity.TM-PF6 could quickly bind to the plasma membrane of bacteria and efficiently kill bacteria.After increased incubation time to 3 h,TM-PF6 moved from cell membrane to mitochondria in cancer cells and triggers mitochondrial apoptosis pathway to induce photodynamic ablation of cancer cells.Finally,in vivo imaging and photodynamic therapy experiments of 4T1 tumor-bearing mouse model were carried out.TM-PF6 demonstrated good retention ability in tumor and could significantly inhibited tumor growth under white light irradiation,which was verified by H&E staining and Ki67 pathological methods.In addition,TM-PF6 has good biocompatibility and hardly has toxic and side effect for the growth of mice and all mice organs.3.Highly efficient photodynamic inactivation of multi-drug resistant bacteria with Isoquinolium-based aggregation-induced emission photosensitizer:Isoquinolium has many advantages such as simple synthesis and tunable properties.Isoquinoline based PS LIQ-TPE with AIE properties was synthesized by modifying the traditional isoquinoline with tetraphenyl ethylene（a representative AIE group）.LIQ-TPE has high ¹O₂ generation efficiency,which is far superior than the most commonly used photosensitizer RB.LIQ-TPE can effectively label Gram-positive and Gram-negative bacteria,and showed good performance in photodynamic ablation of Gram-positive and Gram-negative bacteria and even multi-drug resistant bacteria MRSA,indicating great potential in photodynamic combat of multi-drug resistant bacteria.