Prodrug suicide gene therapy for cancer targeted intracellular by mesenchymal stem cell exosomes

Abstract

AbstractHuman tumor trophic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‒MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‒MSCs contained mRNA of the suicide gene in the exosome’s cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‒fluorocytosine (5‒FC) effectively triggered dose‒dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‒FC to 5‒fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. MSCs transduced with the Herpes simplex virus thymidine kinase gene released exosomes causing death of tumor cells in the presence of ganciclovir. The presence of microRNAs in exosomes produced from naive MSCs and corresponding transgene transduced MSCs did not differ significantly. microRNAs from yCD::UPRT‒MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.