Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths. Unfortunately, there is still no completely effective treatment. Ferroptosis could affect the development of HCC by regulating the level of glutathione (GSH), intracellular lipid peroxidation, and other related substances. This paper introduced a new one-pot reaction for the synthesis of manganese doped mesoporous silica nanoparticles (manganese-silica nanoparticles, MMSNs) which could induce Ferroptosis of the tumor cells through the consumption of intracellular GSH caused by the degradation of MMSNs. The more amount of MnCl₂ added during the preparation, the larger doping amount of manganese presented in MMSNs. When the molar ratio of TEOS to MnCl₂ was 5:1, the prepared MMSNs had a small size (102.6 ± 3.06 nm), uniform structure (pore sizes of 3.67 nm) and large pore volume. Manganese-oxidation bonds of MMSNs could break in high GSH concentration, which in turn consume GSH in the environment rapidly. Sorafenib (SO), an inhibitor of X_c^- transport system was loaded in the MMSNs (MMSNs@SO) with a drug loading rate of 2.68 ± 0.32%. MMSNs@SO achieved on-demand drug release in the tumor microenvironment due to the degradation of MMSNs. Subsequently, a significant tumor cell (HepG2) suppression effect of MMSNs@SO was achieved through the consumption of GSH and synthesis inhibition of intracellular GSH. The depletion of GSH led to the inactivity of Glutathione Peroxidase 4 and increase of intracellular lipid peroxide, which could induce the Ferroptosis of HCC cells. In summary, such dual GSH-exhausting nanodrugs have a great potential to induce Ferroptosis of HCC cells.