功能化阿霉素和铁离子双载羧甲基甲壳素微球通过栓塞、铁死亡和自噬介导的HIF-1α抑制治疗肝细胞癌

Embolic microspheres have been applied in transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), a promising anti-cancer strategy. Herein, our team prepared functional doxorubicin (DOX) and iron ions dual-loaded acrylic acid-grafted carboxymethyl chitin microspheres (CMA) microspheres (CMA/DOX-Fe), whose anti-HCC efficacy, targets, and molecular mechanisms were systematically investigated. The CMA/DOX-Fe were successfully constructed, as characterized by scanning electron microscopy, and exhibited favorable suspension and degradation properties with rapid adsorption of blood cells and procoagulant activity. Crucially, the strong embolic performance and anti-HCC efficacy of CMA/DOX-Fe were confirmed in rabbit models involving the marginal ear vein, renal vessels, and VX2 cell xenografts. Additionally, the CMA/DOX-Fe can trigger ferroptosis and suppress HCC cells by releasing DOX and iron ions, which can also induce autophagy through ATG5 binding. Furthermore, pronounced co-localization of HIF-1α and LC3-lysosomes was observed in the presence of CMA/DOX-Fe, demonstrating autophagy-mediated HIF-1α degradation and downstream signaling inhibition. Finally, the prepared CMA/DOX-Fe demonstrated a favorable safety profile and good biocompatibility. In conclusion, the as-synthesized CMA/DOX-Fe exhibits rapid embolization in HCC with subsequent release of DOX and iron ions, thereby inducing ferroptosis and autophagy. The autophagy-mediated suppression of the HIF-1α signaling pathway blocks metastasis of HCC. The present research provides a novel approach for cancer TACE therapy with embolic microspheres.