Photodynamic Antitumor Activity Of Ga（Ⅲ） And P（Ⅴ） Complexes Of A₂B Type Aryl Corrole

Conventional chemotherapy has severe side effects and is easy to induce drug resistance,which is difficult to meet the clinical needs.Photodynamic therapy（PDT）is a new approach that can effectively treat different types of cancer.PDT has the advantages of low toxicity to normal tissues,small invasion,controllable treatment area selection,low drug resistance,etc.This emerging technology is based on the reaction of photosensitizer（PS）with oxygen molecules in tumor tissue under light irradiation to produce cytotoxic reactive oxygen species（ROS）.Photosensitizer play a key role in photodynamic therapy.Therefore,the development of new photosensitizers is the key to the development of PDT.At present,porphyrin compounds are the most widely used photosensitizers in clinical practices.However,corrole,similar to porphyrin in structure,has attracted extensive attention due to its excellent optical properties in the fields of catalysis,solar cells,and photodynamic therapy.In addition,the corrole can form stable complexes with high-valence metals or nonmetals,and the structures are rich and diverse.Studies have shown that gallium（III）corrole can enter tumor cells with the help of carrier proteins,damage the tumor cytoskeleton,and inhibit cell growth,showing good targeting and cytotoxicity.Monohydroxy gallium（III）corrole exhibites very excellent photodynamic anticancer activity against MDA-MB-231 tumor cells and is low in acute toxicity to mice.The phosphorus（V）corrole also has excellent photodynamic anticancer activity and good biocompatibility.Therefore,the relationship between the structures of corrole and its gallium（III）and phosphorus（V）complexes and their photodynamic antitumor activities has become a hot topic in the research of contemporary antitumor drugs.The balance of hydrophilicity and lipophilicity,low intracellular ROS yield and low biocompatibility have hindered the application of corrole in PDT to some extent.At the same time,single treatment often cannot achieve satisfactory results,and combined therapy is a very promising treatment.On this basis,a series of mono-hydroxy,dihydroxy and trimethoxy A₂B-type aryl corroles and their gallium（III）and phosphorus（V）complexes were designed and synthesized in this paper to study their photodynamic antitumor activities in vitro and in vivo,and the synergistic treatment of cancer with mono-hydroxy phosphorus（V）corrole and nutritional supplement edible bird?s nest was further studied.The main research contents are as follows:（1）10-（2,4-dimethoxyphenyl）-5,15-bis（pentafluorophenyl）corrole（1）and 10-（3,4-dimethoxyphenyl）-5,15-bis（pentafluorophenyl）corrole（2）were synthesized and demethylated to give dihydroxy corroles 10-（2,4-dihydroxyphenyl）-5,15-bis（pentafluorophenyl）corrole（3）and 10-（3,4-dihydroxyphenyl）-5,15-bis（pentafluorophenyl）corrole（4）.3 and 4 were further coordinated to give gallium（III）and phosphorus（V）complexes（3-Ga,4-Ga,3-P and 4-P）.The in vitro photodynamic antitumor activities of 3,4,3-Ga,4-Ga,3-P and 4-P were evaluated.Among them,3-P showed better phototoxicity on A549 and MDA-MB-231 cell lines(IC₅₀,0.081 and 0.116μM)than the photosensitizer Foscan^?(IC₅₀,0.160 and 0.274μM)used clinically.（2）Trimethoxy corroles 10-（2,4,6-trimethoxyphenyl）-5,15-bis（pentafluorophenyl）corrole（5）and 10-（3,4,5-trimethoxyphenyl）-5,15-bis（pentafluorophenyl）corrole（6）and their gallium（III）and phosphorus（V）complexes（5-Ga,6-Ga,5-P and 6-P）were synthesized.Among them,5-P and 6-P showed higher fluorescence intensity,singlet oxygen quantum yield and better photostability.6-Ga,5-P and 6-P exhibited excellent in vivo photodynamic activity against MDA-MB-231,A549,Hela,and Hep G2 cells under 625 nm light,and 6-P showed a higher phototoxicity than Foscan?.Further studies demonstrated that 6-P was rapidly absorbed by Hep G2 cells and mainly accumulated in the cytoplasm.After 6-P photodynamic therapy,Hep G2 cells were observed to have decreased mitochondrial membrane potential,massive intracellular ROS production,nuclear fragmentation,and early and late apoptosis.（3）Mono-hydroxycorroles1,10-（3-bromo-4-hydroxyphenyl）-5,15-bis（pentafluorophenyl）corrole（7）and10-（2-bromo-4-hydroxyphenyl）-5,15-bis（pentafluorophenyl）corrole（8）and their gallium（III）and phosphorus（V）complexes（7-Ga,8-Ga,7-P and 8-P）were synthesized.7-Ga,8-Ga,7-P and 8-P were found to show good photodynamic activity,with 7-P showing the highest phototoxicity and phototoxic index to the cancer cell lines tested,especially to MDA-MB-231 cells(IC₅₀=0.028μM,PI>3571.43).Under the irradiation of 625 nm light,7-P could produce intracellular ROS,destroy mitochondrial membrane potential,and lead to cell apoptosis.Animal experiments showed that7-P photodynamic therapy could effectively inhibit the growth of transplanted MDA-MB-231series BALB/c nude mice tumor tissues and had no significant effect on mouse health.（4）The effect of EBN on the photodynamic antitumor activity of 7-P was studied and the results showed that EBN had no effect on the in vitro photodynamic antitumor activity of 7-P.However,it was found that EBN could promote the therapeutic effect of PDT by enhancing the expression of T cells（such as CD3⁺）at mice level,which provided a certain scientific basis for EBN as a new characteristic medical resource.