Developing a Copper(II) Isopropyl 2‑Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin–Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed a copper (Cu) compound based on the properties of the human serum albumin (HSA)–indomethacin (IND) complex to remodel the tumor microenvironment (TME). We optimized a series of Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds to obtain a Cu(II) compound (C4) with significant cytotoxicity and then constructed an HSA–IND–C4 complex (HSA–IND–C4) delivery system. IND and C4 bind to the hydrophobic cavities of the IB and IIA domains of HSA, respectively. In vivo, the HSA–IND–C4 not only showed enhanced antitumor efficacy relative to C4 and C4 + IND but also improved their targeting ability and decreased their side effects. The antitumor mechanism of C4 + IND involved acting on the different components of the TME. IND inhibited tumor-related inflammation, while C4 not only induced apoptosis and autophagy of cancer cells but also inhibited tumor angiogenesis.