Synthesis And Photodynamic Activities Of Molecular Target-based Anticancer Photosensitizers

Since 1985,application of phthalocyanine in photodynamic therapy(PDT)has attracted considerable attention,phthalocyanine complex is considered to be one of the most promising second-generation photosensitizers for PDT.Molecular target-based anticancer drugs can specifically recognize and kill tumor cells,and therefore become the main categories of anticancer drugs.It is believed that the introduction of the erlotinib moiety to zinc phthalocyanine core can obtain molecular target-based anticancer photosensitizers with high PDT activity and excellent specificity.This study can provide a reference for inaugurating molecular targeted photodynamic therapy and thereby leading to the development of anticancer drugs with high efficient and low toxicity.Based on the reviews on the current research status of phthalocyanine photosensitizers used in PDT and molecular target-based anticancer drugs,two series of molecular target-based anticancer drug-phthalocyanine conjugates with high photodynamic activity and target ability to tumor cells were designed and synthesized.The synthesis,photophysical and photochemical properties and photodynamic activity of these conjugates were investigated.The main works and results are summarized as follows:(1)27 new compounds including 17 intermediates,6 tamoxifen-phthalocyanine conjugates and 4 erlotinib-phthalocyanine conjugates have been synthesized and characterized.All these compounds have not been reported so far.(2)The photophysical and photochemical properties of these conjugates were studied.The UV-Vis spectrum and fluorescence spectrum of these conjugates were investigated.The results showed that conjugates have a significantly red-shifted Q-band(6-8 nm)compared with ZnPc.The length of linker(the polyethylene glycol units)has no significant effect on the photophysical parameters.The substituted position of the phthalocyanine core has no significant effect on the s and aggregation behavior,but influences the ?max abs of Q band,?max em,and ?F.These conjugates are essentially free from aggregation in DMF,and slightly aggregated in the cell culture medium.The quantum yield of singlet oxygen(??)generated by photosensitization is measured.The results showed that the ?? of ?-substituted zinc phthalocyanines was higher than ?-substituted ones.(3)The specificity of these conjugates was investigated at both cell and mice level.The results indicated that all the 6 tamoxifen-phthalocyanine conjugates and 4 erlotinib-phthalocyanine conjugates can target the estrogen receptor(ER)positive and epidermal growth factor receptor(EGFR)over expressed tumor cells/tissues,respectively.(4)The in vitro photodynamic activity of these conjugates was investigated.All these conjugates exhibit high cytotoxicity upon irradiation and essentially non-cytotoxicity with the absence of light.The cellular uptake,reactive oxygen species generation ability and photocytotoxicity are correlated with the length of polyethylene glycol chain and the substituted position.All these 10 conjugates are mainly located in the lysosomes of cells and can effectively distory tumor cells.In summary,the 10 phthalocyanine-based conjugates prepared in this paper are highly promising molecular target-based anticancer photosensitizers.