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.