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: Irina V Balyasnikova, Melanie S Prasol, Sherise D Ferguson, Yu Han, Atique U Ahmed, Margarita Gutova, Alex L Tobias, Devkumar Mustafi, Esther Rincón, Lingjiao Zhang, Karen S Aboody, Maciej S Lesniak
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 22 Issue 1 Pg. 140-8 (Jan 2014) ISSN: 1525-0024 [Electronic] United States
• PMID: 24002694 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Organometallic Compounds
• TNF-Related Apoptosis-Inducing Ligand
• indium oxine
• Oxyquinoline

Topics

• Animals
• Brain Neoplasms (mortality, pathology, therapy)
• Cell Line, Tumor
• Cell Movement
• Cell Tracking
• Chemokine CXCL12 (genetics)
• Disease Models, Animal
• Gamma Rays
• Gene Expression
• Glioma (mortality, pathology, therapy)
• Humans
• Magnetic Resonance Imaging
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice
• Organometallic Compounds
• Oxyquinoline (analogs & derivatives)
• TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Xenograft Model Antitumor Assays