Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and the associated deaths have risen in recent decades. Sorafenib is the first drug to be approved by the Food and Drug Administration (FDA) for routine use in the first-line therapy of patients with advanced HCC. However, only about 30% of patients with HCC will be benefited from sorafenib therapy, and drug resistance typically develops within 6 months. In recent years, the mechanisms of resistance to sorafenib have gained the attention of a growing number of researchers. A promising field of current studies is ferroptosis, which is a novel form of cell death differing from apoptosis, necroptosis, and autophagy. This process is dependent on the accumulation of intracellular iron and reactive oxygen species (ROS). Furthermore, the increase in intracellular iron levels and ROS can be significantly observed in cells resistant to sorafenib. This article reviews the mechanisms of resistance to sorafenib that are related to ferroptosis, evaluates the relationship between ferroptosis and sorafenib resistance, and explores new therapeutic approaches capable of reversing sorafenib resistance in HCC through the modulation of ferroptosis.

Encapsulation of active pharmaceutical ingredients (APIs) in carrier materials for controlled delivery in the desired site is of paramount importance for optimizing the effectiveness of a therapeutic drug while minimizing its side effects. Cucurbit[8]uril (CB[8]) is herein assembled as a host framework to accommodate APIs (tryptophan, phenylalanine biapenem, and diclofenac sodium) in aqueous solution under room temperature to enhance their stability in the gastric acid and realize sustained release in the intestinal tract. Host-guest interactions were investigated by UV-vis spectroscopy while crystal structures of the supramolecular assembly were determined by single-crystal x-ray analysis, which reveals that both the CB[8] framework crystals and the API@CB[8] cocrystals belong to a monoclinic crystal system. With their aromatic rings folded inside the macrocyclic cavity of CB[8] and their alkyl chains stretching outside to interreact with the carbonyl portals of CB [8] through ion-dipole interactions and hydrogen bonding, both hydrophic and hydrophobic APIs were readily encapsulated inside the supramolecular framework. In comparison to API in its free form, an accelerated dissolution kinetic of the API@CB[8] cocrystals was observed at intestinal pH (6.8), which otherwise demonstrated a lower dissolution profile at gastric pH (1.5). With their biocompatibility confirmed by cytotoxicity test, the proposed pharmaceutical cocrystals provide a new paradigm for intestine-targeted drug delivery.