title: Extracellular vesicle-mediated suicide mRNA/protein delivery inhibits glioblastoma tumor growth in vivo.
abstract: Extracellular vesicles (EVs) are considered as important mediators of intercellular communication, which carry a diverse repertoire of genetic information between cells. This feature of EVs can be used and improved to advance their therapeutic potential. We have previously shown that genetically engineered EVs carrying the suicide gene mRNA and protein-cytosine deaminase (CD) fused to uracil phosphoribosyltransferase (UPRT)-inhibited schwannoma tumor growth in vivo. To further examine whether this approach can be applied to other cancer types, we established a subcutaneous xenograft glioblastoma tumor model in mice, as glioblastoma represents the most common primary brain tumor, which is highly aggressive compared with the original schwannoma tumor model. U87-MG glioblastoma cells were implanted into the flanks of nude SCID mice, and the animals were intratumorally injected with the EVs isolated from the cells expressing EGFP or CD-UPRT. After the intraperitoneal administration of the prodrug 5-fluorocytosine, the tumor growth was assessed by regular caliper measurements. Our data revealed that the treatment with the CD-UPRT-enriched EVs significantly reduced the tumor growth in mice. Taken together, our findings suggest that EVs uploaded with therapeutic CD-UPRT mRNA/protein may be a useful tool for glioblastoma treatment.
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: E P
authors.initials: EP
authors.lastname: Erkan
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Senfter
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Madlener
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Jungwirth
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Ströbel
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Saydam
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Saydam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001692:Biological Transport; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D000067128:Extracellular Vesicles / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology; D012333:RNA, Messenger; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D011355:Prodrugs; D012333:RNA, Messenger; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase