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.