Synthesis And In Vitro Photodynamic Activities Of The Multi-Functional Anticancer Photosensitizers

Photodynamic therapy(PDT)is a noninvasive,highly selective method for the destruction of unwanted cells and tissues.PDT consists of three essential components:a photosensitizer,light and oxygen,each of them is indispensable for PDT application.Photosensitizers,which play a vital role in PDT process,decide the efficiency of PDT.Phthalocyanines,as one class of the most promising second-generation photosensitizers,have intense absorptions in the red region betAveen 650 and 800 nm,are capable of producing excited triplet and singlet oxygen efficiently,show good chemical stability,can be easily modified.However,they are still low tumor-targeting compounds,which limit their application in terms of PDT.In this thesis,to improve selectivity of PDT and realize combination of PDT and chemotherapy,several active molecules with tumor-targeting or chemotherapeutic have been conjugated to the zinc(II)phthalocyanine core.Their photo-physical,-chemical and-biological properties have been studied.Chapter ? gives an overview to photodynamic therapy and photosensitizers,including the mechanism and development of PDT.Furthermore,chemotherapy and its combination application with PDT are also introduced in this chapter.In addition,the development and the brief introduction of the "click chemistry" have been presented.Chapter ? describes the synthesis and characterization of biotin-zinc(II)phthalocyanine-coumarin conjugates(12a,13a)and a reference compound 3a.The photophysical and photochemical properties and in vitro photodynamic activities of all these compounds have been studied.The results show that:introduction of biotin and coumarin moieties has no significant effect on the photophysical and photochemical properties of both conjugates;They are not aggregated significantly in the cell culture medium;The singlet oxygen quantum yield(??)of 12a and 13a are 0.60 and 0.59 respectively;Both conjugates exhibit high photocytotoxicity against MCF-7 cancer cell;the introduction of biotin and coumarin has also enhanced the effect of photodynamic therapy and chemotherapy,realizing the combination use of them.These two drugs are mainly located in lysosome and mitochondria of MCF-7 cells.Chapter ? presents the synthesis and characterization of a new zinc(II)phthalocyanine derivative 4b.The photophysical and photochemical properties as well as the in vitro photodynamic activities of 4b and the reference compound 3a have also been explored.The results show that:both of them are not aggregated significantly in the cell culture medium,they have a similar maximum absor:ption wavelength(?maxem),fluorescence quantum yield(?F)and singlet oxygen quantum yield(??);The targeting conjugates exhibit a relative high photocytotoxicity against MGF-7 and HepG2 cancer cells,their IC50 value are 0.95 and 1.25 ?M respectively;The cellular uptakes of 4b in the MCF-7 and HepG2 cancer cells are much more than those in HELF normal cells.This drug is mainly located in lysosome and mitochondria of MCF-7 and HepG2 cells.~1H NMR and HRMS spectra of all the new compounds are given in Appendix.