LAUSR

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.