Development of a High-Efficacy and Low-Toxicity Cobalt(II) Agent for Targeting Inhibition of Tumor Growth through Mitochondrial Damage-Mediated Chemotherapy and Immunotherapy
Minghui Zhu, Shihang Xu, Guochao Li, Gang Xu, Zhenlei Zhang, Hong Liang, Feng Yang
Abstract
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.