Thiol-Triggered Release of Intraliposomal Content from Liposomes Made of Extremophile-Inspired Tetraether Lipids

Liposomal drug-delivery systems have been used for delivery of drugs to targeted tissues while reducing unwanted side effects. DOXIL, for instance, is a liposomal formulation of the anticancer agent doxorubicin (DOX) that has been used to address problems associated with nonspecific toxicity of free DOX. However, while this liposomal formulation allows for a more-stable circulation of doxorubicin in the body compared to free drug, the efficacy for cancer therapy is reduced in comparison with systemic injections of free drug. A robust liposomal system that can be triggered to release DOX in cancer cells could mitigate problems associated with reduced drug efficacy. In this work, we present a serum-stable, cholesterol-integrated tetraether lipid comprising of a cleavable disulfide bond, {GcGT(S–S)PC–CH}, that is designed to respond to the reducing environment of the cell to trigger the release intraliposomal content upon cellular uptake by cancer cells. A cell viability assay revealed that DOX- loaded lipos...