Intranasal Stem-Cell Based Therapy of Glioblastoma

Project: Research project

Description

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: To examine the efficacy of MSCs expressing TRAIL, an oncolytic virus, or
a ph-responsive nanoparticle in different models of malignant glioma in vivo.
StatusActive
Effective start/end date4/1/163/31/20

Funding

  • National Institute of Neurological Disorders and Stroke (5R01NS087990-05)

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Glioblastoma
Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Stem Cells
Cell Movement
Nasal Cavity
Oncolytic Viruses
Neoplasms
Biological Therapy
Tropism
Brain
Biological Products
Photons
Brain Neoplasms
Glioma
Pharmaceutical Preparations
Nanoparticles
Microscopy
Therapeutics
Magnetic Resonance Imaging