Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy

Abstract

Although promising, the efficiency of aggregation-induced emission luminogens (AIEgens)-based photodynamic therapy (PDT) is limited by cellular glutathione (GSH). GSH is not a terminal reducing agent but it can be oxidized and subsequently reduced to its original state by reductases to further participate in antioxidant activity. It is therefore imperative to control GSH for effectively inducing oxidation within tumor cells. Recent studies showed that tumor cell metabolism depends mainly on glutamine, which is also the nitrogen and ATP source for GSH synthesis. Therefore, glutamine-based starvation therapy may be effective in enhancing photodynamic therapy. In this work, tumor-derived exosomes were developed for co-delivering AIEgens and proton pump inhibitors (PPI) for tumor combination therapy. Tumor-derived exosomes could specifically deliver drugs to the tumor sites, where PPI inhibited cell glutamine metabolism, suppressed tumor cell GSH and ATP production, and improved the effect of type-I PDT from AIEgens. When used in the treatment of MGC803 gastric cancer subcutaneous model, our system shows a high tumor growth inhibition rate, and even promoting tumor immunogenic death. This is the first work which combine inhibition of glutamine metabolism with PDT, and it has the potential to be applied for future designs of new tumor metabolic therapies and photodynamic systems.

Keywords: Aggregation-induced emission luminogens; Enhanced type-I photodynamic therapy; Glutamine starvation therapy; Proton pump inhibitors; Tumor-derived exosomes.