Synthesis And In Vitro Photodynamic Activities Of Drugs Combining Targeted Photodynamic Therapy With Chemotherapy

Photodynamic Therapy(PDT)is a new non-invasive therapy for tumor diseases.Compared with traditional therapies,it has many advantages.However,PDT is a local treatment and is not suitable for the treatment of large or metastatic tumors.The combination of PDT and chemotherapy can not only enhance the killing effects on tumors and metastatic tumors,but also reduce the side effects of chemotherapy drugs and overcome the multidrug resistance of tumor cells.Phthalocyanine photosensitizer has the advantages of long and strong red absorption,high quantum yield of singlet oxygen,easy modification of structure and so on,which has been recognized as a potential second generation anticancer photosensitizer.However,its targeting uptake of tumor cells is not high,which limits its application in PDT.Therefore,improving the targeting of photosensitizer and enhancing the combination of PDT and chemotherapy have become a hot topic in the field of PDT.In this paper,we have reported a kind of phthalocyanine compounds with targeting,PDT and chemotherapeutic properties,and studied their photophysical,photochemical and biological activities.Chapter 1 briefly introduces the development of PDT and photosensitizers,and summarizes the factors that affect the properties of phthalocyanine photosensitizer.Meanwhile,the basic situation of targeted therapy and chemotherapy,as well as the application of PDT combined with chemotherapy in the treatment of cancer are also introduced.Chapter 2 describes the synthesis and characterization of Biotin-ZnPc-Coumarin conjugate and the reference compounds Coumarin,ZnPc-OH and ZnPc-Coumarin.Moreover,their photophysical and photochemical properties and oil-water partition coefficient are also studied.The results have showed that all these three kinds of phthalocyanine compounds have good photo-stability in DMF and cell culture medium,and they share similar photo-physical and photo-chemical properties.Biotin-ZnPc-Coumarin and ZnPc-Coumarin exist mainly in monomeric form in cell culture medium,while the ZnPc-OH aggregation is more serious.All of them have similar fluorescence quantum yield(0.17,0.14 and 0.14)and singlet oxygen quantum yield(0.74,0.81 and 0.77)in DMF;According to the distribution coefficient of lipid and water,they all showed the amphipathy.Chapter 3 studies the in-vitro photodynamic activities of all these compounds,as well as their control compounds.Three photosensitizers,ZnPc-OH,ZnPc-Coumarin and Biotin-ZnPc-Coumarin have showed higher photodynamic anticancer activity.(The IC50 values are 0.71,0.12 and 0.26 M,respectively).The photodynamic anticancer activity of ZnPc-Coumarin and Biotin-ZnPc-Coumarin are significantly higher than that of ZnPc-OH,and they show a similar dark toxicity with Coumarin.The uptake of Biotin-ZnPc-Coumarin in MCF-7 is significantly higher than that in HELF,suggesting that the introduction of biotin and coumarin can improve the targeting and anticancer activity of zinc phthalocyanine photosensitizer and achieve the joint anti-tumor effect of PDT targeted therapy and chemotherapy.ZnPc-OH and ZnPc-Coumarin are mainly distributed in lysosomes and mitochondria after being absorbed by MCF-7 cells.Biotin-ZnPc-Coumarin is mainly distributed in lysosomes,but not in the nucleus.