A Tumor-Activatable Sorafenib Prodrug for Alleviating Hypoxia and Enhancing Hepatocellular Carcinoma Therapy

Sorafenib (Sfb) is a widely used chemotherapy drug for the clinical treatment of hepatocellular carcinoma (HCC); however, its therapeutic effect is often hindered by inherent nonspecific toxicity and hypoxia-induced epithelial–mesenchymal transition (EMT). Besides, its inhibition of tumor angiogenesis further aggravates hypoxia, intensifying this challenge. Herein, we have developed a tumor-activatable Sfb prodrug (Sfb-Fca) to reverse the hypoxic tumor microenvironment for EMT alleviation and enhance therapeutic outcomes in HCC. Sfb-Fca consists of two components: the major moiety (Sfb) and the ferrocene acid (Fca) moiety, linked via a thioketal bond. This bond is cleaved in the presence of the elevated H 2 O 2 levels typical of cancer cells, releasing Sfb for chemotherapy and Fca for hypoxia modulation. Fca catalyzes the production of O 2 via a Fenton-like reaction, alleviating tumor hypoxia, reducing intracellular levels of HIF-1α and ZEB1 protein, and synergistically enabling effective chemodynamic therapy for enhancing the therapeutic effects of Sfb.