Developing a Multitargeted Anticancer Bi-Copper(II)-Centered Thiocarbohydrazone Agent Based on Lys-199 and His-242 Residues in the IIA Subdomain of Human Serum Albumin

To develop the next generation of more efficient anticancer metal therapeutics and simultaneously achieve targeted therapy, we proposed to develop a bimetallic-centered agent that utilizes the properties of human serum albumin (HSA). To this end, a series of bi-copper (Cu)-centered thiocarbohydrazone compounds were optimized to obtain a bi-Cu(II)-centered compound (C3) with remarkable cytotoxicity. Subsequently, we not only constructed a novel HSA–C3 complex delivery system but also determined the structure of the HSA–C3 complex. Importantly, the HSA–C3 complex inhibits tumor growth more effectively (inhibition rate = 74.20%) than C3 alone (inhibition rate = 48.71%) while enhancing the tumor-targeting ability and reducing the in vivo side effects of C3. Furthermore, we confirmed that the C3 and HSA–C3 complex inhibits tumor growth by not only inducing tumor cell apoptosis but also dual activating the immune system by blocking the PD-1/PD-L1 interaction and resetting tumor-associated macrophages toward the M1 phenotype.