Developing a Multitargeted Anticancer Palladium(II) Agent Based on the His-242 Residue in the IIA Subdomain of Human Serum Albumin

To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.