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

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.