Small Organic Molecules As Fluorescent Probes For Tumor Targeted Imaging And Therapy

A fluorescent probe,i.e.,a fluorescent sensing molecule,is a molecular measuring device that continuously transforms the chemical information of the analysis object into a measurable fluorescence signal by molecular recognition.With the popularization of fluorescence microscopy in the field of bio-imaging and clinical therapy,fluorescence imaging technology based on fluorescence probe and microscope has been widely studied.It has become a common method of biological analysis,and a powerful tool for observing cell morphology,structure and other life related phenomenon.Besides surgery,radiotherapy,chemotherapy and biological therapy,phototherapy has become an important alternative therapy for cancer.Photodynamic therapy(PDT)has the advantages of minimally invasive,low toxicity,quick recovery and high selectivity.With a series of photosensitizers approved to be suitable for clinical and laser medical system,PDT becomes a promising therapy.In this thesis,we aimed to synthesis a series of small organic molecules capable of transmitting near infrared fluorescence,to achieve specific optical change in tumor microenvironment,to obtain more obvious fluorescent signals and to realize the imaging of tumor cells.Further,the covalent bonds of linkers and excellent photosensitizing abilities of small molecules are used to achieve the goal of photodynamic therapy and improve the therapeutic effect.We finally build a novel integrated mode of cancer diagnosis and treatment based on small organic molecules.First,a heptamethine cyanin dye molecule(Cy.7.Cl)was synthesized.Based on our previous studies,it is promising to be a targeted and fluorescence imaging moiety.Then,Cy.7.Cl are linked to other functional mollecules through disulfide bonds to obtain several small molecule fluorescent probes with reductive response and pH response abilities(Cyss Cy,CyssTPP,IR808ssIR808,IR808NN).Molecular structure modification has been used to obtain organic molecules(IR1048-MZN)with near infrared two region fluorescence imaging characteristics and redox response potential.Finally,the CyssTPP molecule was applied to fluorescence imaging and targeted photodynamic therapy in vitro and in vivo,and achieved great diagnosis and treatment effects.The experimental results show that in a certain range,with the increase of the GSH(reduced glutathione)in CyssTPP solution,there will be a characteristic fluorescence peak with an increase of the intensity equal ratio around 800 nm,showing the ability of the small molecule to be a fluorescent probe of GSH;further,we have been in the subsequent photodynamic experiment in vitro.It was found that the reactive oxygen specie(ROS)production of the CyssTPP group was higher than the sum of the Cy.7.Cl and TPP groups,which showed the potential of the molecule as a photosensitizer with a synergistic photodynamic therapy,and the cell level experiment showed that the molecular probe could enrich the non-targeting TPP photosensitizers in mitochondrion,which is a good target for photodynamic therapy.The well-defined molecular probe also greatly improves high-contrast fluorescence imaging and high-efficient PDT therapeutics in vivo.Since then,we have successfully constructed a series of multifunctional organic small molecular probes with tumor targeting,imaging diagnosis,tumor microenvironmental response,and robust phototherapy,which is of great value to the extension of tumor precision treatment.