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.