Lysosomes activating chain reactions against cancer cells with a pH-switched prodrug/procatalyst co-delivery nanosystem

Abstract

Conventional chemotherapy uses potent toxic drugs to destroy cancer cells and always causes severe systemic toxicity in patients. In this respect, a smart and pH-switched prodrug/procatalyst co-delivery nanosystem is developed which is non-toxic toward normal cells and is inert during its delivery in the vasculature, while responsively functions in acidic lysosomes inside cancer cells. Synthetically, non-toxic artemisinin (ART) was used as the prodrug and loaded into the inner space of hollow mesoporous silica (HMS) nanoparticles (NPs). Subsequently, Fe₃O₄ NPs were efficiently capped onto pore outlets of HMS via acid labile acetal linkers (ART@HMS-Fe₃O₄). ART@HMS-Fe₃O₄ was stable under neutral conditions (pH 7.4) with almost no leakage of ART. Upon exposure to the acidic lysosomal compartment (pH 3.8–5.0) in cells, the acetal linkers were hydrolyzed which led to sustained release of both ART and Fe₃O₄ NPs. Under the activation of the lysosomal environment, the liberated Fe₃O₄ NPs were metabolized to free iron ions and catalyzed the generation of high amounts of free radicals from the released ART in cells. In vitro cytotoxicity assay revealed excellent anticancer efficacy of this ART/Fe₃O₄ co-delivery nanosystem. The Fe₃O₄ NPs acted both as gatekeepers and procatalysts which inhibited ART from leakage during their delivery, while released ART and activated chain reactions to form free radicals in acidic lysosomes inside cancer cells. We visualize that this lysosomal environment-responsive ART@HMS-Fe₃O₄ nanosystem could serve as an efficient and desirable chemotherapeutic nanosystem for cancer therapy.