Synthesis,Antitumor Activity And Mechanism Of Thiosemicarbazone Gallium(Ⅲ) Complexes And Quinoline Gallium(Ⅲ) Complex Nano-Drugs

Ga（Ⅲ）has been proved to have the ability to inhibit tumor growth,so it can be transformed into Gallium chelate to improve bioavailability and low toxicity.It makes Ga（Ⅲ）become a research hotspot in the new field of metal complex anticancer drugs.In this paper,gallium（Ⅲ）complexes were synthesized based on thiosemicarbazone ligands,and their antitumor activity and mechanism were studied in vitro.In addition,based on the previous research of our group,tris（5-bromo-8-hydroxyquinoline）gallium（Ⅲ）complex（K6）with high toxicity to HCT116 and low biocompatibility has been proposed to synthesize nano-drugs through a simple"one-pot"method,which to solve drug delivery difficulties for metal-organic complexes.The in vitro and in vivo of antitumor activity for nano-drugs were compared.The main research contents are as follows:（1）A series of thiosemicarbazone ligands and their gallium（Ⅲ）complexes were synthesized and characterized.The anticancer activity of gallium（Ⅲ）complexes were better than cisplatin which studied by MTT method.Among them,glyoxal bis（thiosemicarbazone）gallium（G1）has the best inhibitory activity on HCT116 cell and MDA-MB-231 cell,and its inhibitory concentration(IC₅₀ value)reaches the n M level;3,4-hexanedione bis（thiosemicarbazide）gallium（G4）has excellent selectivity for MDA-MB-231 cell and very low toxicity to normal cells.The anti-tumor mechanism of G1 and G4 was further studied,and it was found that the level of intracellular reactive oxygen species（ROS）increased after drug treatment,which caused the cell cycle to stay in different periods,resulting in a decrease in mitochondrial membrane potential and activation of mitochondrial apoptosis pathway,eventually leading to cancer cell apoptosis.At the same time,the strong interaction between the complex and protein disulfide isomerase（PDI）at the molecular level was observed by means of molecular simulation docking experiments.（2）Based on early research of our groups,gallium nano-drugs were synthesized combined with the effective anticancer agent Ga（Ⅲ）complex K6,which using bovine serum albumin（BSA）and graphene oxide（GO）as drug carriers.Nanoparticles of K6@BSA and K6@GO were prepared with sizes of about 110 nm and 669 nm by a simple"one-pot method"at room temperature and under microwave conditions.It can maintain stable existence in aqueous solution.Cytotoxicity experiments show that the two nano-drugs have excellent anti-proliferative effects on HCT116 cells,and the intracellular ROS level and apoptosis ratio are also better than those of the clinical drug oxaliplatin.The further mice animal experiments showed that the tumor-targeting performance of GO nanoparticles was better than that of BSA nanoparticles.This paper provides a new research idea for how to improve drug delivery in vivo and enhance anti-tumor activity of metal-organic complexes with poor biocompatibility.