👤 Matović ZD.

Title: Endoplasmic reticulum-targeted iridium(III) photosensitizer induces pyroptosis for augmented tumor immunotherapy. Abstract: An ideal tumor treatment strategy involves therapeutic approaches that can enhance the immunogenicity of the tumor microenvironment while simultaneously eliminating the primary tumor. A cholic acid-modified iridium(III) (Ir3) photosensitizer, targeted to the endoplasmic reticulum (ER), has been reported to exhibit potent type I and type II photodynamic therapeutic effects against triple-negative breast cancer (MDA-MB-231). This photosensitizer induces pyroptotic cell death mediated by gasdermin E (GSDME) through photodynamic means and enhances tumor immunotherapy. Mechanistic studies have revealed that complex Ir3 induces characteristics of damage-related molecular patterns (DAMPs) in MDA-MB-231 breast cancer cells under light conditions. These include cell-surface calreticulin (CRT) eversion, extracellular high mobility group box 1 (HMGB1) and ATP release, accompanied by ER stress and increased reactive oxygen species (ROS). Consequently, complex Ir3 promotes dendritic cell maturation and antigen presentation under light conditions, fully activates T cell-dependent immune response in vivo, and ultimately eliminates distant tumors while destroying primary tumors. In conclusion, immune regulation and targeted intervention mediated by metal complexes represent a new and promising approach to tumor therapy. This provides an effective strategy for the development of combined targeted therapy and immunotherapy. Show less

By rational altering the structure of CN auxiliary ligand, Near-infrared (NIR) phosphorescent cyclometalated platinum (II) and iridium (III) complexes with metformin (Met) have been successfully obtained and characterized. The dissociation of Met in aqueous solution can be accelerated by addition of Glutathione (GSH) and alleviated by drop of histidine, accompanied with a significant decay change of deep red phosphorescence. Besides, Pt3 and Ir1 with moiety of btpq mainly selectively targeted and located in Mitochondrial, while Pt1 of ppy and Pt2 with thpy mainly accumulated in endoplasmic reticulum. Moreover, Pt1-3 and Ir1 with metformin moiety all exert a significant enhanced anticancer activity, among them, Pt3 displays ca.66-fold, ca.147-fold and ca.588-fold higher cytotoxicity than cisplatin, Met-free analogue Pt3a and Met. Their relative anticancer mechanism was further investigated, both Pt2 and Pt3 could form covalent interaction with bovine serum albumin (BSA) and effectively induce reactive oxygen species (ROS) generation, arrest of cell cycle, loss of Mitochondrial membrane potential (MMP), display effective anti-metastasis activity and eventually induce apoptosis of cancer cell. Show less