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In this study, we proposed to design effective multi-target anticancer agents based on the chelation of nontoxic metals with ligands that possess anticancer activity. In total, five Sn(ii) pyridine-2-carboxaldehyde thiosemicarbazone complexes are synthesized and their activities are tested. Among these complexes, C5 is found to show the highest cytotoxicity on investigating their structure-activity relationships. In addition, C5 not only exhibits an effective inhibitory effect against tumor growth in vivo, but also suppresses angiogenesis and restricts the metastasis of cancer cells in vitro. Multiple mechanisms underlie the antitumor effect of C5, and they include acting against DNA, inducing apoptosis, and inhibiting the activities of anti-apoptotic Bcl-xL protein, metalloproteinase MMP2 and topoisomerase II.

On the one hand, to obtain a novel next-generation anticancer metal agent; on the other hand, to improve the targeting ability and decrease side effects of metal agent, we proposed to design active-targeting human serum albumin (HSA) nanoparticles (NPs) to achieve the end. Thus, we not only designed and synthesized two ruthenium (Ru) thiosemicarbazone compounds (C1 and C2) but also succeeded in constructing active Biotin-HSA NPs for Ru(III) compounds. Importantly, Biotin-HSA-C2 NPs not only possessed a stronger capacity for killing MCF-7 cells and inhibiting their migration versusC2 alone but also increased accumulation compared to non-malignant WI-38 cells. Additionally, C2 and Biotin-HSA-C2 NPs act against MCF-7 cells by the following potential mechanism: 1) arresting the cell cycle in the S phase by regulating cyclin and cyclin-dependent kinases; 2) inducing apoptosis by releasing cytochrome c to activate caspase-9/3; 3) inhibiting the expression of p-EGFR and regulating its neighboring cellular pathways, followed by the inactivation of PI3K/Akt and activation of p38 MAPK signaling pathways.