Developing a Vanadium(IV) Complex for Targeted Inhibition of Growth and Metastasis of Tumors by Multiacting on Cancer Cells and Dual Activating Immune System

To overcome the limitations of platinum (Pt)-based drugs and achieve the targeting inhibition of tumor growth and metastasis, we optimized a series of vanadium (V, IV) 4,6-diacetylresorcinol thiosemicarbazone complexes to obtain a V(IV) complex (V5) with remarkable cytotoxicity (IC50 = 1.25 ± 0.41 μM) by investigating their structure–activity relationships in SK-OV-3 cell. V5 demonstrated greater cytotoxicity compared to the Pt thiosemicarbazone complexes we previously synthesized (IC50 = 4.23 ± 0.74 μM against SK-OV-3 cells). We then constructed a V5-AFt nanoparticles (NPs) delivery system. In vivo results showed that V5 and AFt-V5 NPs not only effectively inhibited tumor growth (Inhibition rates = 49.3% and 63.6%, respectively) and metastasis, but also AFt NPs enhanced the tumor-targeting ability of V5 and reduced its side effects. Furthermore, we confirmed that the mechanism of V5/AFt-V5 NPs inhibiting tumor growth and metastasis involved not only multiaction on cancer cell by damaging mitochondrion, inducing apoptosis and ferroptosis, and dual regulating glucose metabolism, but also the dual activation of the immune system by inducing lactic acid-mediated macrophage repolarization and inducing ferroptosis-mediated immunogenic cell death.