title: Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery.
abstract: Glioblastoma multiforme (GBM) is one of the most intractable of human cancers, principally because of the highly infiltrative nature of these neoplasms. Tracking and eradicating infiltrating GBM cells and tumor microsatellites is of utmost importance for the treatment of this devastating disease, yet effective strategies remain elusive. Here we report polymeric nanoparticle-engineered human adipose-derived stem cells (hADSCs) overexpressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as drug-delivery vehicles for targeting and eradicating GBM cells in vivo. Our results showed that polymeric nanoparticle-mediated transfection led to robust up-regulation of TRAIL in hADSCs, and that TRAIL-expressing hADSCs induced tumor-specific apoptosis. When transplanted in a mouse intracranial xenograft model of patient-derived glioblastoma cells, hADSCs exhibited long-range directional migration and infiltration toward GBM tumor. Importantly, TRAIL-overexpressing hADSCs inhibited GBM growth, extended survival, and reduced the occurrence of microsatellites. Repetitive injection of TRAIL-overexpressing hADSCs significantly prolonged animal survival compared with single injection of these cells. Taken together, our data suggest that nanoparticle-engineered TRAIL-expressing hADSCs exhibit the therapeutically relevant behavior of "seek-and-destroy" tumortropic migration and could be a promising therapeutic approach to improve the treatment outcomes of patients with malignant brain tumors.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fitch
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305.
authors.forename: Christine
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305.
authors.forename: Christy
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Stanford University, Stanford, CA 94305.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Grant
authors.affiliation: Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305; fanyang@stanford.edu.|Department of Bioengineering, Stanford University, Stanford, CA 94305.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
mesh_terms: D017667:Adipocytes / Q000637:transplantation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D033581:Stem Cell Transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000235:genetics*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: TRAIL; adipose-derived stem cells; glioblastoma; nanoparticle; tumor microsatellites