Developing a Novel Indium(III) Agent Based on Liposomes to Overcome Cisplatin-Induced Resistance in Breast Cancer by Multitargeting the Tumor Microenvironment Components

To overcome the resistance of cancer cells to platinum-based drugs and effectively suppress tumor growth, we developed a novel indium (In) agent based on liposomes (Lips). Thus, we not only obtained an In­(III) thiosemicarbazone agent (5b) with remarkable cytotoxicity by optimizing a series of In­(III) thiosemicarbazone agents (1b–5b) but also successfully constructed a novel 5b-loaded Lip (5b-Lip) delivery system. Importantly, in vitro and in vivo results revealed that 5b/5b-Lip overcame the tumor cell resistance and effectively inhibited MCF-7/DDP tumor growth. In addition, Lips improved the intracellular accumulation of 5b. We also confirmed the mechanism by which 5b/5b-Lip overcomes breast cancer cell resistance. 5b/5b-Lip cannot act against DNA in cancer cells but attacks the two cell components in the tumor microenvironment, namely, by inducing apoptosis and lethal autophagy of cancer cells and resetting tumor-promoting M2 macrophages to the tumor-killing M1 phenotype.