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 H2O2 levels typical of cancer cells, releasing Sfb for chemotherapy and Fca for hypoxia modulation. Fca catalyzes the production of O2 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.