Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis

Abstract

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex ( 4b ) with remarkable cytotoxicity in vitro but also constructed a 4b -decitabine (DCT)/liposome (Lip) delivery system ( 4b -DCT-Lip). The in vivo results showed that 4b -DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b -DCT but also addressed the co-delivery problems of 4b -DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b -DCT/ 4b -DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b -activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response.