Developing a Copper(II) Agent Based on His-146 and His-242 Residues of Human Serum Albumin Nanoparticles: Integration To Overcome Cisplatin Resistance and Inhibit the Metastasis of Nonsmall Cell Lung Cancer

To overcome the resistance of nonsmall
cell lung cancer (NSCLC)
cells to cisplatin and inhibit their metastasis, we proposed to develop
a Cu­(II) agent based on the specific residue(s) of HSA nanoparticles
(NPs) for multitargeting the tumor microenvironment (TME). To this
end, we not only synthesized four Cu­(II) 2-hydroxy-3-methoxybenzaldehyde
thiosemicarbazone compounds (C1–C4), obtaining a Cu compound
(C4) with significant cytotoxicity by studying their structure–activity
relationships, but also revealed the binding mechanism of C4 to HSA
through X-ray crystallography and confirmed the successful construction
of a new HSA-C4 NPs delivery system. C4 and HSA-C4 NPs inhibited the
A549cisR tumor growth and metastasis, and HSA NPs optimized the anticancer
behavior of C4. We further confirmed the anticancer mechanism of the
C4/HSA-C4 NP multitargeting TME to overcome cisplatin resistance:
killing tumor cells by acting on the mtDNA and inducing apoptosis,
polarizing M2-type macrophages to the M1-type, and inhibiting angiogenesis.