Development Of NIR Aggregation-Induced Emission Luminogens For Multimodal Tumor Theranostics

The morbidity and mortality of cancer are increasing year by year and have become the biggest health risk worldwide.The development of tumor imaging techniques provides important tools and methods for precise diagnosis and treatment of tumor.However,the existing clinical tumor imaging techniques have certain limitations,which make it difficult to realize the classification and treatment of different patient groups.Additionally,the separation of diagnosis and treatment process also causes the difference of treatment outcome.With the progress of research on tumor theranostics,personalized medicine is gradually coming to the clinic,which requires the development and use of theranostic drugs with high specificity,high stability,high biosafety and outstanding therapeutic effects.The emerging aggregation-induced emission(AIE)luminogens demonstrate enhanced fluorescence emission in the aggregate state,high stability and fluorescence quantum yield,and good biocompatibility,showing a broader prospect for biological applications compared with traditional fluorescent materials.Additionally,AIE luminogens can be designed and optimized to realize therapeutic functions for tumor theranostics.Nonetheless,fluorescence imaging has limited tissue penetration depth,which makes it difficult to detect deep tissue lesions with noninvasive imaging.To solve this problem in this thesis,on the one hand,the penetration ability of fluorescence imaging was enhanced by extending the absorption and emission wavelengths of the fluorescent probes;on the other hand,fluorescence imaging was combined with radionuclide imaging to play a complementary role and provide more comprehensive structural and functional information.In addition,not only the fluorescencence properties of the AIE materials could be modulated,but also the outstanding photosensitivity or chemotoxic effects were endowed to the AIE materials through structural optimizations in this thesis,thus enabling the combination of imaging and multiple therapeutic functions to exert their potential for tumor theranostics.In the second chapter,NIR AIE photosensitizers with A-π-D-π-A structure was designed to provide a diversified and more efficient design strategy for the development of AIE photosensitizers.Most of the reported AIE photosensitizers are designed with D-π-A or D-(π)-A-(π)-D structures,while AIEgens with A-(π)-D-(π)-A structures are rarely reported probably owing to the relatively difficult synthesis process.By introducing the triphenylamine structure as a strong electron donor with rotor effect,thiophene as a π-conjugated linker unit and a weak electron donor,and cyanostyrene and pyridine groups as strong electron acceptors,the fluorescent molecules with strong AIE effect were prepared to achieve efficient NIR fluorescence emission and exhibit excellent photosensitization ability.The AIEgen was encapsulated by polymers to form water-soluble nanoparticles,which could be efficiently taken up by tumor cells and effectively kill tumor cells through the photodynamic effect.In the third chapter,a NIR-Ⅱ AIE probe based on the A-π-D-π-A structure was developed to realize efficient fluorescence imaging both in vitro and in vivo.By introducing a stronger electron acceptor unit benzindole salt,an AIEgen with bright NIR-Ⅱ fluorescence emission was prepared.The AIEgen was encapsulated by polymers to form water-soluble nanoparticles,which could be efficiently taken up by tumor cells in vitro and tumors in vivo.The selective aggregation of the AIE probe in mitochondria caused cellular oxidative stress and activation of caspase 3,which in turn led to GSDME cleavage and activation of cell pyroptosis.The inflammatory factors released from the pyroptotic cells resulted in pro-immunostimulatory effects that could enhance the anti-tumor immune response in vivo,thus enabling the combaination of AIE probe and immune checkpoint therapy to exert powerful anti-tumor immunotherapeutic effects.In the fourth chapter,to further enhance the diagnostic function of the AIE probe,the 18F radionuclide was combined with an AIEgen to produce a NIR radiolabeled AIE probe,which could be rapidly and efficiently taken up by tumor cells and selectively aggregated in mitochondria after entering tumor cells to effectively induce cell apoptosis,resulting in a prominent chemotherapy effect on tumor cells.However,the fluorescence imaging sensitivity of the AIE probe was lower than that of PET imaging,requiring the use of both radioactive and non-radioactive AIE probes to achieve effective implementation of both imaging modalities.Additionally,the problem of water solubility of the probe could also impose important limitations on the concentration used.In the fifth chapter,to improve the water solubility of the radiolabeled AIE probe,a NIR-Ⅱ AIE probe was designed and developed with enhanced fluorescence imaging and therapeutic functions.The AIEgen was encapsulated by polymers to form watersoluble nanoparticles,which were subsequently chelated with 68Ga radionuclides to achieve radionuclide labeling.The probe could be efficiently taken up by tumor cells in vitro and tumors in vivo,and the photothermal conversion of the AIEgens could be be efficiently activated under laser irradiation locally to achieve efficient tumor photothermal therapy guided by fluorescence/PET dual-modality imaging.However,the probe showed high uptake in multiple organ tissues in vivo,which reduced tumor uptake efficiency.In the sixth chapter,a polymer-decorated NIR-Ⅱ AIEgen was designed and developed to reduce in vivo organ accumulation of the radiolabeled AIE probe and enhance tumor uptake and therapy efficiency.The AIEgens could self-assemble to form stable quantum dots(ca.9.5 nm),which were subsequently chelated with 177Lu radionuclides to achieve radionuclide labeling.The probe could persistently accumulate at tumor site in vivo(≥4 days),while the uptake in the organs was low,thus enabling high-contrast fluorescence/SPECT imaging and efficient synergistic tumor photothermal and radionuclide therapy.In this paper,several novel AIE probes were developed from the orientations of molecular structure design and functional applications.Different imaging and therapeutic functions were conferred to the AIE probes through structural optimizations,leading to various application studies in tumor fluorescence imaging,radionuclide imaging and chemotherapy,photodynamic therapy,photothermal therapy,immunotherapy and radionuclide therapy.The efficacy of these AIE probes for tumor theranostic applications has been systematically evaluated from in vitro to in vivo.These works play a significant role in promoting the development of multifunctional AIE probes and the achievement of precise tumor theranostics to meet the life and health needs of people.