Bioactive Aggregation-induced Emission Materials:Synthesis And Applications In Imaging And Therapy

Organic luminescent materials have the advantages of facile synthesis,adjustable structure and light colors,and low cost.They have been widely used in many fields such as photoelectronic devices,chemical sensing,biological probes,medical diagnosis and treatment.However,the traditional organic luminescent materials often possess a largeπconjugated plane,which leads to the phenomenon of aggregation caused quenching（ACQ）in the solid or the aggregate state,limiting their practical application.The aggregation-induced emission（AIE）has fundamentally solved the difficult problem of ACQ,which provided a novel idea for the development and application of new materials.At present,abundant research achievements have been made in the field of AIE,but with the deepening understanding of AIE,there are still some challenges.For example,in the development of new material system,most AIE luminogens（AIEgens）are developed according to the mechanism of restriction of intramolecular rotation（RIR）,and there are few new AIE material systems developed according to restriction of intramolecular vibration（RIV）.Strong hydrophobic AIEgens are prone to aggregation and sedimentation in biological water environment,so the development of a new water-soluble AIEgens is more in line with the needs of biological applications.In addition,targeting imaging and therapy of AIEgnes usually are realized by connecting targeting groups.It will be simpler and more effective for targeting imaging and therapy to find novel AIEgens with self-targeting and biological activity.Based on the above research background,the research contents of this thesis are as follows:In Chapter 2,a series of novel cationic AIEgens that are comprised of tricyclic 2-aminopyridinium derivatives are designed and synthesized according to the mechanism of RIV.Notably,these cationic AIEgens exhibit the ability to specifically stain gram-positive bacteria.Moreover,a specific AIEgen,BMTAP-7,possesses highly efficient bacteriostatic ability for Staphylococcus aureus（S.aureus）in both liquid medium and solid agar plates,which have a minimum inhibitory concentration（MIC）between 4 and 8μg m L^-1.These AIEgens with bacteriostatic activity hold great promise for distinguishing between bacterial types and inhibiting bacterial infections in situ.In Chapter 3,a class of commercialized antibiotics were identified with higher antibacterial activity and biological targeting,such as levofloxacin（LEV）,norfloxacin（NOR）,and moxifloxacin hydrochloride（MXF-HCl）,featuring the unique AIE characteristics.By taking advantage of their AIE feature,antibiotic metabolism in cells could be in situ visualized,which clearly shows that the luminescent aggregates accumulate in the lysosomes.Moreover,after a structure-activity relationship study,we found an ideal site of MXF to be modified with a triphenylphosphonium and an antibiotic derivative MXF-P was prepared,which is able to specifically differentiate bacterial species after only 10 min of treatment.Moreover,MXF-P shows highly effective broadspectrum antibacterial activity,excellent therapeutic effects and biosafety for S.aureus-infected wound recovery.Thus,this work not only discovers the multifunctionalities of the antibiotics but also provides a feasible strategy to make the commercialized drugs more powerful.In Chapter 4,an AIE photosensitizer was covalently attached to the antibiotic of moxifloxacin hydrochloride（MXF-HCl）and an antibiotic derivative,MXF-R,was synthesized with pharmacological activity and photodynamic activation.In infected cells,MXF-R showed enhanced fluorescence after it specifically binds to bacteria;thus,in situ visualization of the bacteria was realized.Notably,through chemo-and photodynamic therapy,MXF-R exhibited better antibacterial activity than its parent antibiotic in rapid sterilization,and it achieved effective killing for moxifloxacin resistant bacteria.In addition,MXF-R shows a broad-spectrum antibacterial effect and could be used in the recovery therapy of infected wounds in mice,demonstrative of a significant therapeutic effect and good biological safety.This work provides an innovative strategy for solving critical disease through the combination of materials and biomedical sciences.In Chapter 5,MXF-R was applied the in the targeted imaging of fungal vacuolar membranes and antifungal therapy.MXF-R was used to identify Candida albicans in mixed strains by the difference in staining ability of MXF-R to various strains.Furthermore,compared with the commercial membrane dye FM4-64,MXF-R demonstrated a higher signal-to-noise ratio,stronger targeting capability,and better biocompatibility.Using MXF-R’s ability to target vacuole membranes,in situ visualization of vacuole formation was achieved during Candida albicans proliferation.In addition,strong ROS production capacity of MXF-R was used to kill Candida albicans,which was significantly more effective than the commercial drug Fluconazole.Therefore,MXF-R is a multi-functional fluorescent probe and it is very promising as a reagent for the rapid diagnosis and treatment.In Chapter 6,the bioactive group alkynamide was introduced into the AIE molecule and realized a specific reaction of alkynylamides with thiol group in the presence of amine group by reducing the activity of activated alkynes.Notably,MBTB-PA,an AIEgen with an alkynylamide unit,was synthesized and used for protein labeling in the physiological environment.Subsequently,the intracellular behavior of MBTB-PA was visualized in situ by fluorescence imaging,demonstrating its excellent ability to target the endoplasmic reticulum.Furthermore,this reaction occurred in tumor cells and consumed reductive substances such as GSH,causing tumor cell death due to intracellular oxidative stress.Based on this reaction therapy strategy,MBTB-PA achieved effective killing of tumor cells through ferroptosis in vitro and in vivo.Therefore,this work provides feasible ideas for the application research of bioactive materials in cells.