Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors

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

doi:10.1038/mt.2013.199

Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors

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

^*Corresponding author for this work

Neurological Surgery

Research output: Contribution to journal › Article › peer-review

96 Scopus citations

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. 111 In-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.

Original language	English (US)
Pages (from-to)	140-148
Number of pages	9
Journal	Molecular Therapy
Volume	22
Issue number	1
DOIs	https://doi.org/10.1038/mt.2013.199
State	Published - Jan 2014

Funding

This work was supported by the Elsa U. Pardee Foundation (I.V.B.), ACS IL. Div. (I.V.B.) and in part by the NIH grants R01 CA138587 (M.S.L.), NIH R01 CA122930 (M.S.L.), NIH R01 NS077388 (M.S.L.), NIH U01 NS069997 (M.S.L.), by pilot research funding provided by the Virginia and D. K. Ludwig Fund for Cancer Research via the Imaging Research Institute in the Biological Sciences Division of the University of Chicago. K.S.A. is chief scientific officer at TheraBiologics. The other authors declare no conflict of interest.

ASJC Scopus subject areas

Drug Discovery
Genetics
Molecular Medicine
Molecular Biology
Pharmacology

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Balyasnikova, I. V., Prasol, M. S., Ferguson, S. D., Han, Y., Ahmed, A. U., Gutova, M., Tobias, A. L., Mustafi, D., Rincón, E., Zhang, L., Aboody, K. S., & Lesniak, M. S. (2014). Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors. Molecular Therapy, 22(1), 140-148. https://doi.org/10.1038/mt.2013.199

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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. 111 In-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.",

author = "Balyasnikova, {Irina V.} and Prasol, {Melanie S.} and Ferguson, {Sherise D.} and Yu Han and Ahmed, {Atique U.} and Margarita Gutova and Tobias, {Alex L.} and Devkumar Mustafi and Esther Rinc{\'o}n and Lingjiao Zhang and Aboody, {Karen S.} and Lesniak, {Maciej S.}",

note = "Funding Information: This work was supported by the Elsa U. Pardee Foundation (I.V.B.), ACS IL. Div. (I.V.B.) and in part by the NIH grants R01 CA138587 (M.S.L.), NIH R01 CA122930 (M.S.L.), NIH R01 NS077388 (M.S.L.), NIH U01 NS069997 (M.S.L.), by pilot research funding provided by the Virginia and D. K. Ludwig Fund for Cancer Research via the Imaging Research Institute in the Biological Sciences Division of the University of Chicago. K.S.A. is chief scientific officer at TheraBiologics. The other authors declare no conflict of interest.",

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doi = "10.1038/mt.2013.199",

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AU - Balyasnikova, Irina V.

AU - Prasol, Melanie S.

AU - Ferguson, Sherise D.

AU - Han, Yu

AU - Ahmed, Atique U.

AU - Gutova, Margarita

AU - Tobias, Alex L.

AU - Mustafi, Devkumar

AU - Rincón, Esther

AU - Zhang, Lingjiao

AU - Aboody, Karen S.

AU - Lesniak, Maciej S.

N1 - Funding Information: This work was supported by the Elsa U. Pardee Foundation (I.V.B.), ACS IL. Div. (I.V.B.) and in part by the NIH grants R01 CA138587 (M.S.L.), NIH R01 CA122930 (M.S.L.), NIH R01 NS077388 (M.S.L.), NIH U01 NS069997 (M.S.L.), by pilot research funding provided by the Virginia and D. K. Ludwig Fund for Cancer Research via the Imaging Research Institute in the Biological Sciences Division of the University of Chicago. K.S.A. is chief scientific officer at TheraBiologics. The other authors declare no conflict of interest.

PY - 2014/1

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N2 - 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. 111 In-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.

AB - 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. 111 In-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.

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Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors

Abstract

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