Developing a Molybdenum(IV) Agent Based on a Specific N-Donor Residue in Human Serum Albumin IB Subdomain: Multi-Targeted Inhibition of Growth and Metastasis in Hepatocellular Carcinoma

Abstract To achieve the targeted inhibition of hepatocellular carcinoma (HCC) growth and metastasis, we optimized a series of molybdenum (Mo) compounds to obtain a Mo(IV) 2-acetylquinoxaline thiosemicarbazone compound (Mo5) with remarkable cytotoxicity, and constructed a Mo5-human serum albumin (HSA) complex delivery system (Mo5−HSA). Structural analysis revealed that Mo5 binds to the IB subdomain of HSA, where His146 replaces a Cl ligand of Mo5 and coordinates with the Mo center. The Mo5−HSA complex exhibited improved inhibitory efficacy against HCC growth and metastasis, enhanced targeting ability and reduced side effects in vivo compared with Mo5. Furthermore, we confirmed that Mo5 and Mo5−HSA inhibit tumor growth and metastasis through multiple effects on the tumor microenvironment, including the induction of mitochondrial dysfunction, apoptosis and autophagy in cancer cells, disruption of cellular lipid metabolism, and activation of immunogenic cell death-mediated immune response.