Synthesis And Anti-Tumor Activity Of Selenium-Based Organic Small Molecule Photosensitizer

Cancer is a major threat to human health.Improving the efficiency of treatment and reducing the side effects of treatment have become an urgent need for cancer treatment.Photodynamic therapy（PDT）has attracted more and more attention due to its advantages of non-invasive,safety and high selectivity.As an effective adjuvant therapy for cancer,PDT is beneficial to improve the quality of life of cancer patients.In the process of PDT,photosensitized agents（PSs）transition to the lowest excited singlet state（S₁）after exposure to light,and rapidly transition to the excited triplet state（T₁）with a long life through interline crossing（ISC）,and interact with molecular oxygen to produce cytotoxic reactive oxygen species（ROS）.However,traditional photosensitizers are difficult to synthesize,have unstable molecular structure,small Stokes shift,poor water solubility and dark toxicity,which are not conducive to the generation of T₁ state,resulting in their ineffective anti-tumor effects in the process of PDT.Introducing heavy atom Se into large conjugated system is beneficial to spin orbit coupling（SOC）mediated ISC,which can effectively improve the T₁ state yield of PSs and increase ROS production,so that PSs can better exert PDT effect.Due to the complex synthesis of heavy atom selenium,it is of great significance to develop selenium-containing organic small molecule photosensitizers with simple synthesis and high ROS generation efficiency.In this paper,three novel electronic push-pull organic small molecule photosensitizers BSN,NSN and PSN were synthesized.BSN,NSN and PSN can produce reactive oxygen species（ROS）,and the ROS generation capacity of BSN and NSN is stronger than that of PSN.BSN,NSN and PSN can all produce singlet oxygen（¹O₂）,and the singlet oxygen subyields（Φ_Δ）of BSN,NSN and PSN are 0.089,0.086 and 0.13,respectively.Both BSN and PSN have the ability to generate hydroxyl radical（·OH）,and the·OH generating capacity of BSN is stronger than that of PSN.BSN,NSN and PSN accumulate on mitochondria and lysosomes and induce ROS production under light.Mitochondrial membrane potential decline indicated that ROS caused mitochondrial damage,indicating that BSN,NSN and PSN could induce cell apoptosis.MTT assay showed that BSN,NSN and PSN had low dark toxicity and strong phototoxicity in normal and cancer cells.Among them,BSN has the best killing effect in cancer cells.2μM BSN can reduce the survival rate of Hep G2 cells by 90%under light,showing good PDT effect.In order to improve the biocompatibility and targeting ability of BSN,BSN and DSPE-PEG2000 were packaged according to the mass ratio of 1:1,1:2,1:3,1:4 and 1:5.BSN@NP1,BSN@NP2,BSN@NP3,BSN@NP4 and BSN@NP5 were obtained.Scanning electron microscopy（SEM）showed that the nanostructures synthesized in different proportions were rod-like or irregular aggregates.Using DPBF as an indicator,theΦ_Δof BSN@NPs are 0.25,0.23,0.46,0.41 and 0.36,respectively.The ¹O₂ generation efficiency of the wrapped material is significantly improved.By comparing the test results,we found that the nanostructures synthesized by 1:3 mass ratio BSN@NP3 have uniform dispersion,stable structure and high¹O₂ quantum yield.TMB chromogenic experiment showed that it could induce the production of·OH in the slightly acidic environment of tumor by light.The results showed that BSN@NP3 can be used as an excellent photosensitizer with both type I and type II photosensitizer.After incubation in normal cells and cancer cells,BSN@NP3 was found to accumulate in cancer cells.BSN@NP3 can locate the mitochondria of cancer cells.ROS produced under light induces cell apoptosis and causes mitochondrial damage.When 30μM BSN@NP3 was added,the survival rate of normal cells was 90%and that of cancer cells was as low as 10%.The experiment showed that BSN@NP3 could effectively improve the targeting ability of BSN to tumor cells,reduce the phototoxicity of normal cells,and realize the highly selective PDT process of tumor cells.The experimental results showed that the organic small molecule photosensitizer BSN,NSN and PSN containing selenium synthesized based on electron push-pull structure could all produce ROS under light,and BSN was more phototoxic and had the best killing effect on cells.The nanostructure formed by DSPE-PEG2000 encapsulation increases the biocompatibility of BSN,among which BSN@NP3 synthesized by 1:3 feeding can not only improve the ¹O₂ quantum yield,but also enhance tumor targeting,effectively improving the PDT performance of small molecule photosensitized BSN.