title: Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors.
abstract: Treatment options of glioblastoma multiforme are limited due to the blood-brain barrier (BBB). In this study, we investigated the utility of intranasal (IN) delivery as a means of transporting stem cell-based antiglioma therapeutics. We hypothesized that mesenchymal stem cells (MSCs) delivered via nasal application could impart therapeutic efficacy when expressing TNF-related apoptosis-inducing ligand (TRAIL) in a model of human glioma. ¹¹¹In-oxine, histology and magnetic resonance imaging (MRI) were utilized to track MSCs within the brain and associated tumor. We demonstrate that MSCs can penetrate the brain from nasal cavity and infiltrate intracranial glioma xenografts in a mouse model. Furthermore, irradiation of tumor-bearing mice tripled the penetration of (¹¹¹In)-oxine-labeled MSCs in the brain with a fivefold increase in cerebellum. Significant increase in CXCL12 expression was observed in irradiated xenograft tissue, implicating a CXCL12-dependent mechanism of MSCs migration towards irradiated glioma xenografts. Finally, MSCs expressing TRAIL improved the median survival of irradiated mice bearing intracranial U87 glioma xenografts in comparison with nonirradiated and irradiated control mice. Cumulatively, our data suggest that IN delivery of stem cell-based therapeutics is a feasible and highly efficacious treatment modality, allowing for repeated application of modified stem cells to target malignant glioma.
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Prasol
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Sherise D
authors.initials: SD
authors.lastname: Ferguson
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Atique U
authors.initials: AU
authors.lastname: Ahmed
authors.affiliation: Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Margarita
authors.initials: M
authors.lastname: Gutova
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Tobias
authors.affiliation: Department of Radiology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Devkumar
authors.initials: D
authors.lastname: Mustafi
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Rincón
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Aboody
authors.affiliation: Department of Surgery, The Brain Tumor Center, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058948:Cell Tracking; D054377:Chemokine CXCL12 / Q000235:genetics; D004195:Disease Models, Animal; D005720:Gamma Rays; D015870:Gene Expression; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009942:Organometallic Compounds; D015125:Oxyquinoline / Q000031:analogs & derivatives; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D054377:Chemokine CXCL12; D009942:Organometallic Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C032950:indium oxine; D015125:Oxyquinoline