Construction of pH-responsive nanocarriers in combination with ferroptosis and chemotherapy for treatment of hepatocellular carcinoma

Abstract

Abstract Background Chemotherapy is widely used to treat hepatocellular carcinoma (HCC). Although sorafenib (SO) is the only chemotherapy drug approved by FDA for treatment of HCC, it is associated with several disadvantages including low water solubility, low bioavailability, lack of targeting and easily causes systemic toxicity. In recent years, nanocarriers have shown promise in drug delivery to effectively solve these problems. Herein, we used SO-loaded nanocarriers to overcome the defects of chemotherapy during treatment of HCC. Specifically, we encapsulated pH-sensitive hollow mesoporous Prussian blue nanoparticles (HMPB) with SO (an inhibitor of multi-kinase and accelerant of ferroptosis) to act as carriers and facilitate drug release. We also coated its surface with a layer of pH-responsive chitosan (CS) to block the drug and increase biocompatibility. Finally, we successfully constructed HP/SO/CS nanocomposites for targeted delivery of chemotherapeutic drugs, with the aim of initiating chemotherapy and ferroptosis for dual treatment of tumors. In vitro and in vivo experiments were performed for evaluation of the nanocomposites’ anti-tumor efficacy by using liver cancer cells and mice, respectively. Results The nanocomposites specifically targeted tumor cells through enhancing permeability and retention (EPR) effect. Results from in vitro experiments showed that the nanocarriers not only promoted cell apoptosis and reduced the number of cells for chemotherapy, but also promoted accumulation of reactive oxygen species (ROSs). In vivo experiments showed that mice in the nanocomposite-treated group exhibited the smallest tumor sizes and body weights, with no obvious damage to normal tissues and organs. Conclusion Taken together, these findings indicated that nanocarriers had an effective inhibitory effect on HCC cells. This safe and multifunctional treatment model was a valuable option for the treatment of HCC, as well as other cancers. Graphical Abstract

Keywords

• Ferroptosis
• Hepatocellular carcinoma
• Prussian blue
• Sorafenib