Design And Synthesis Of Organic Fluorescent Dyes For Cancer Diagnosis And Photodynamic Therapy

Naphthalamide.benzophenoxazine.and benzophenothiazine derivatives are promising for biological applications including bioimaging and photodynamic therapy.These dyes have efficient photochemical,physical properties,and high fluorescence quantum yield.The subject of this thesis is to design and synthesize functional dyes based on naphthalamide,benzophenoxazine,and benzophenothiazine for cancer diagnosis,and photodynamic therapy.(1)Firstly,biomarker targeted fluorescent probes are needed crucially to overcome difficulties in the early detection of cancer.We designed and synthesized naphthalimide conjugated probe(NP-C6-CXB)to detect the cvclooxygenase-2(COX-2)enzyme in cancers,based on the conjugation of naphthylamide(identification group)with celecoxib(targeting group),via a flexible hexylene-diamine linker.NP-C6-CXB shows bright fluorescence in solution and cancer cells in the presence of COX-2 with excellent selectivity.Due to the selective binding affinity of NP-C6-CXB with COX-2 enzyme,the intensity is proportional to the level of COX-2 enzyme in cancer cells.In vivo and in vitro experiments proved that NP-C6-CXB has substantial penetrating ability into tumor tissue and tumor site in mice.providing an opportunity as a conceivable tool for identification and discrimination of COX-2 expressed tumors.(2)Similarly,celecoxib conjugated henzophenoxazine dye(Nile blue)(NB-C6-CCB)was synthesized for the detection of COX-2 enzyme with near-infrared emission(700 nm).NB-C6-CCB displayed active fluorescence at near-infrared wavelength(700 nm)in tumor cells and tumor tissues with high expression of COX-2.Subcellular localization of NB-C6-CCB has preferentially pointed the Golgi apparatus and stimulates the intensity at an elevated level,suggesting that NB-C6-CC13 is a potential probe for imaging of COX-2 expressed cancer cells.(3)Photodynamic therapy-based cancer ablation provides a selective cancer therapy with less toxicity.Hercin,we designed and synthesized benzophenothiazine based NIR alkylated cationic photosensitizers(Et-NB-C12,Mt-NB-C 12,Et-NB-C18,and Mt-NB-C18)for ablation of tumor cells through reactive oxygen species(major O2-· and minor 1O2)generation via PDT irradiation.The O2-· radical and 1O2 sensors exhibited ten folds increment of fluorescence intensity in solutions and MCF-7 cells after the treatment with NIR cationic photosensitizers under 660 nm of irradiation.These NIR cationic photosensitizers are consolidated perfectly with commercial lyso-membrane tacker in MCF-7 cells as its preferential target.This leads to generate the ROS in lyso-membranes to abolish the cancer proliferation by lysosomal apoptosis pathway.In particular,Et-NB-C12 presented outstanding anticancer properties during in vitro and in vivo cancer treatments.