Charge Switchable Intelligent Theranostic Platform For Imaging-guided Precision Antibacterial Therapy

Bacteria are highly adaptive and renewable,easily lead to food,medical equipment and other pollution and cause serious infectious diseases.As a common clinical treatment for bacterial infection,the overuse of antibiotics results in the emergence of drug-resistant bacteria,weakening the therapeutic effect.Phototherapy,especially photothermal therapy and photodynamic therapy,becomes a promising treatment method due to the advantages of a wide antibacterial spectrum and no drug resistance.However,most therapeutic systems are based on the integration of individual photothermal transduction agent and photosensitizer,and even require two-wavelength excitation light irradiation,resulting in asynchronous treatment,superimposed side-effect.Besides,most therapeutic agents have poor water solubility,short blood circulation time,lack of bacterial targeting and specificity,resulting in poor therapeutic effect and non-specific damage to normal tissues.In this thesis,an intelligent theranostic platform based on near-infrared photothermal/photodynamic-in-one agent and guanidinium-based covalent organic nanosheet was designed and fabricated for fluorescence imaging-guided chemo/photothermal/photodynamic synergistic sterilization.The main results are as follows:An intelligent theranostic platform（iCON@NIR-PT-PD）based on near-infrared photothermal/photodynamic-in-one agent（NIR-PT-PD）and guanidinium-based covalent organic nanosheet（iCON）was prepared.The pH-reversibly activated NIR-PT-PD was designed with a symmetric cyanine dye as the parent compound by introducing the hydroxyethyl piperazine as specific recognition site for bacteria-targeting and the carboxyl group to provide self-assembly sites and increase hydrophilicity.Meanwhile,iCON was prepared as the auxiliary bactericidal agent and the nanocarrier.iCON@NIR-PT-PD intelligent theranostic platform was subsequently fabricated via electrostatic self-assembly of the above NIR-PT-PD and iCON.The zeta potential of iCON@NIR-PT-PD was-26.7±0.4m V in the simulation of normal humoral environment（pH 7.4）,while 29.3±0.9 m V in the simulation of bacterial weaken acid microenvironment（pH 6.0）with charge reversal,ensuring the intelligent targeting.Meanwhile,NIR-PT-PD was separated from iCON,resulting in fluorescence recovery and specific activation of photothermal and photodynamic properties.The p Ka and pH sensitivity range of NIR-PT-PD were 6.3 and 5.5-7.5,respectively,which were basically consistent with the acidic microenvironment of bacteria,ensuring the feasibility of bacteria-specific imaging and treatment.iCON@NIR-PT-PD kept the pH reversible activation characteristics and the ability to produce heat and singlet oxygen（¹O₂）,and further improved the stability of NIR-PT-PD,laying a foundation for bacterial-targeted imaging and synergistic sterilization.The targeted imaging and high antibacterial efficiency of iCON@NIR-PT-PD were demonatrated.The results of laser confocal scanning microscope showed that iCON@NIR-PT-PD had a good bacterial-specific targeting and prolonged the blood circulation time of NIR-PT-PD.The antibacterial efficiency of iCON@NIR-PT-PD against Escherichia coli and Staphylococcus aureus was almost 100%under the irradiation of 808 nm laser(0.6 W cm^-2,10 min),better than that of iCON and NIR-PT-PD.The bactericidal effect of iCON@NIR-PT-PD was related to the production of ¹O₂which was comfirmed by DCFH-DA indicator,providing the possibility for the application of iCON@NIR-PT-PD in the treatment of bacterial infection.iCON@NIR-PT-PD was applied for in vivo targeted imaging-guided precision chemo/photothermal/photodynamic synergistic therapy.Compared with NIR-PT-PD and iCON,iCON@NIR-PT-PD had better biocompatibility.In vivo fluorescence imaging showed that iCON@NIR-PT-PD had excellent bacteria-specific targeting ability and prolonged blood circulation.In addition,iCON@NIR-PT-PD gave a good therapeutic effect on Staphylococcus aureus-infected mice without obvious changes in body weight and organ necrosis,providing a prospective strategy for the design of more intelligent bacterial infection treatment platform.