Intranasal delivery of drugs has attracted attention as a promising delivery strategy to the central nervous system (CNS). Drugs or other biologics can be delivered directly and locally to the brain by the application to the nasal cavity thereby avoiding complications associated with the BBB and invasive surgery. Given the tropism of mesenchymal stem cells (MSCs) to brain tumor, there is significant interest in utilizing these cells as therapeutic vehicles. As shown in our most recent publication in Molecular Therapy, MSCs expressing TRAIL and delivered to the nasal cavity travel to intracranial tumors in mice and significantly prolong survival. However, in spite of these promising results, our studies have revealed several limitations that need to be addressed before this therapy is clinically relevant. First, very few stem cells (<5%) reach the brain following intranasal delivery and the majority accumulate in the lungs. Second, imaging of stem cell- based therapeutics is still in its infancy and the development of FDA-approved agents is critical for in vivo applications. Third, very little is known about the kinetics of stem cell migration and quantification of stem cell- based therapies following intranasal delivery. As a result, we propose to address these three problems while examining mechanistic pathways of MSCs migration in the CNS to test the central hypothesis: """"""""Intranasal delivery of MSCs can be optimized for clinical applications and allow for safe and repeated administration of biological therapies in the context of GBM."""""""" In order to test this hypothesis, we now propose to complete the following specific aims:
Specific Aim 1 : To characterize the migration of MSCs following intranasal administration using magnetic resonance imaging (MRI) and single photon emission microscopy (SPEM).
Specific Aim 2 : To determine the role of hypoxia on MSC migration and tumor infiltration in vivo.
Specific Aim 3 : To evaluate the role of irradiation on MSC migration and tumor infiltration in vivo.
Specific Aim 4 : T examine the efficacy of MSCs expressing TRAIL, an oncolytic virus, or a pH-responsive nanoparticle in different models of malignant glioma in vivo.

Public Health Relevance

The development of efficient strategies to deliver therapeutics to high-grade brain tumors is critically needed due to the poor clinical efficacy of currently available treatments. This proposal seeks to evaluate intranasal delivery of mesenchymal stem cells for brain tumor therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS087990-01
Application #
8738225
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fountain, Jane W
Project Start
2014-07-01
Project End
2019-03-31
Budget Start
2014-07-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cheng, Shih-Hsun; Yu, Dou; Tsai, Hsiu-Ming et al. (2016) Dynamic In Vivo SPECT Imaging of Neural Stem Cells Functionalized with Radiolabeled Nanoparticles for Tracking of Glioblastoma. J Nucl Med 57:279-84
Dey, Mahua; Yu, Dou; Kanojia, Deepak et al. (2016) Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma. Stem Cell Reports 7:471-82
Spencer, Drew A; Young, Jacob S; Kanojia, Deepak et al. (2015) Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy. Ther Deliv 6:453-68
Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A et al. (2015) Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. Stem Cells 33:2985-94