Development of a High-Efficacy and Low-Toxicity Cobalt(II) Agent for Targeting Inhibition of Tumor Growth through Mitochondrial Damage-Mediated Chemotherapy and Immunotherapy

To overcome the deficiencies of platinum agents and the targeted inhibition of tumor growth, we proposed to develop a high-efficacy and low-toxicity cobalt (Co) agent multiacting on tumor cells based on the properties of the tumor microenvironment and liposomes (Lip). To this end, we optimized a series of Co(II) α-N-heterocyclic thiosemicarbazone complexes to obtain a Co(II) complex (C3) with significant cytotoxicity against tumor cells in vitro through an investigation of their structure–activity relationships and then constructed a C3-Lip delivery system. In vivo results showed that, on the one hand, C3/C3-Lip effectively inhibits tumor growth with almost no toxic side effects; on the other hand, C3-Lip improves the therapeutic efficiency and targeting ability of C3. Besides, we confirmed the mechanism by which C3/C3-Lip inhibits tumor growth: they do not act on DNA in tumor cells but rather damage tumor cell mitochondrion, disrupt respiratory function to block energy metabolism, and induce immunogenic cell death.