An ultra-high disulfiram-loaded delivery system achieved by supercritical carbon dioxide technology for copper-enhanced chemotherapy

Disulfiram (DSF) is a conventional alcohol-aversion drug that has recently been explored as a chemotherapeutic agent and has shown excellent anticancer activity in cooperation with Cu2+ ions. However, the existing DSF delivery system has multiple shortcomings, including low drug loading and Cu2+ delivery efficiency, hindering its clinical applicability. Here, we demonstrated a simple but efficient strategy for realizing the controllable loading of hydrophobic DSF into Cu2+-doped mesoporous silica nanoparticles (Cu-MSN) by using supercritical CO2 technology with ultra-high drug loading efficiency. Benefiting from the unique environment of high pressure and solubility, DSF was well dispersed in supercritical CO2 and immersed into the carriers with controllable drug loading. Factorial experiments indicated an optimal condition (55 °C, 250 bar, and 6 h) for the DSF loading up to 30.8 %. In vitro and in vivo experiments demonstrated high Cu2+-enhanced chemotherapeutic efficacy of DSF. In particular, in cooperation with Cu2+ ions in MSN, the formation of complex (CuET) greatly enhanced and prolonged the antitumor effect. Together, our findings indicated that DSF-loaded Cu-MSN prepared using supercritical solvent impregnation (SSI) enhanced the antitumor effect and had potential in anticancer therapy.