Impairing antioxidant protection by diminishing hyaluronic acid using nanoliposomes for tumor therapy

Abstract

H₂O₂ plays a significant role in tumor development. However, tumor cells possess certain protective mechanisms that reduce the cytotoxic effects of H₂O₂. Researchers have observed a notable increase in the expression of hyaluronic acid (HA), which possesses antioxidant properties, within the tumor microenvironment. This investigation revealed that HA can mitigate oxidative damage to tumors. In response to exogenous H₂O₂, tumor cells enhance their production of HA as a mechanism to counteract external oxidative stress. The suppression of HA levels through hyaluronidase or ribavirin significantly heightened the cytotoxic effects of H₂O₂ and led to an accumulation of intracellular reactive oxygen species (ROS), ultimately inhibiting tumor cell proliferation. A formulation known as H₂O₂@Lip + Rib@Lip was developed, utilizing liposomes encapsulated with H₂O₂ and ribavirin, and was tested in murine models. The results indicated a significant reduction in tumor volume in the H₂O₂@Lip + Rib@Lip treatment group compared to the H₂O₂@Lip and Rib@Lip groups. Furthermore, these findings were accompanied by decreased levels of HA and CD44 receptors, increased levels of H₂O₂, and enhanced apoptosis within the tumor tissues. Therefore, in the context of ROS and related therapies, HA should be prioritized as it serves as the primary and rapid antioxidant barrier in cells. Blocking HA metabolism presents a potential strategy for enhancing oxidative stress therapy.