Study On The Photodynamic Anticancer Activity Of Monohydroxyl Corroles And Their Metal Complexes

Photodynamic therapy(PDT)is a noninvasive therapeutic modality for the treatment of a variety of cancerous tumors and non-cancerous diseases,such as lung cancer,prostate cancer,age-related macular degeneration and infection diseases.This emerging technique requires a non-toxic photosensitizer(PS)which can generate reactive oxygen species(ROS)under harmless light source in the presence of molecular oxygen.As compared to surgery or radiation therapy,PDT has significant advantages in virtue of negligible systemic toxicities and minimal toxicity to normal tissue.The PS plays a crucial role in determining the efficiency of PDT.Porphyrin derivative is a kind of the most studied photosensitizer.Corroles are an aromatic tetrapyrrolic macrocycle similar to porphyrin.Corroles have the ability to stabilize high-valent central metal ion,typical photophysical properties(high molar extinction coefficient and fluorescence quantum yield),and large NH acidities.The application of corroles and metallocorroles as photosensitizers in PDT has developed rapidly.The effect of hydrophilicity and lipophilicity on the PDT activity of corroles is an important topic.To continue our efforts in studying corroles for use in PDT,here we report the preparation of a series of mono-hydroxyl corroles and their complexes,their PDT effect were also investigated.The main research content is as follows:(1)A series of iron(III),manganese(III)and copper(III)mono-hydroxyl corrole complexes had been prepared and well characterized by UV–vis,¹H NMR,¹⁹F NMR and HR-MS.These metallocorroles may bind to CT-DNA through external binding mode.Metallocorrole Fe3exhibited significant phototoxicity and low toxicity toward A549 tumor cells.All tested metallocorroles exhibited nontoxicity to human normal cells(GES-1)with or without irradiation at 625 nm.Cell cycle analysis indicated that metallocorrole Fe3 arrested the cell cycle at G2/M phase and increased the Sub-G1 phase in A549 cell lines.It was mainly localized at mitochondria and could significantly reduce mitochondrial membrane potential after photodynamic treatment,which would further induce tumor cell apoptosis.(2)Three mono-hydroxy corroles 1-3 and their gallium(III)complexes Ga1-Ga3 were synthesized,and their photodynamic antitumour activities towards breast cancer cells were investigated.All corroles showed excellent cytotoxicity against the MDA-MB-231 and 4T1 cell lines upon light irradiation at 625 nm.Ga3 exhibited excellent phototoxicity and selectivity against MDA-MB-231 cells,with an IC₅₀ of 0.06±0.03 m M and a selective index value of1338.83(relative to human normal Huvec cells).The performance of Ga3 was even better than that of the clinical photodynamic therapy drug m-THPC.A preliminary mechanistic investigation revealed that corrole 3 and Ga3 were mainly located in the cytoplasm.Upon irradiation,they could generate intracellular reactive oxygen to destroy the mitochondrial membrane potential and arrest the cell cycle at the sub-G1 phase.Flow cytometry revealed that corrole 3 and Ga3 induced cancer cell apoptosis after photodynamic treatment.Corrole 3 and Ga3 displayed negligible cytotoxicity in the dark.(3)Corrole 3-PEG conjugates and Ga3-PEG conjugates have been synthesized and characterized.Based on the amphiphilic character of the conjugates,they were found to undergo self-assembly into nanostructures(NP3 and NPGa3)with size 80 nm.The PDT activities of NP3 and NPGa3 in vivo were also assessed in human breast tumor xenografts in nude mice.It showed that exhibited excellent anti-tumor ability.(4)In order to improve the treatment efficacy and reduce the side effects,the synergistic therapy has been effectively exploited in cancer treatment.Herein,we reported a kind of acid-sensitive drug delivery system for synergistic therapy,in which chemotherapeutics doxorubicin co-assembled with photosensitizer 3 and Ga3.