Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma.
The challenges to effective drug delivery to brain tumors are twofold: (1) there is a lack of non-invasive methods of local delivery and (2) the blood-brain barrier limits systemic delivery. Intranasal delivery of therapeutics to the brain overcomes both challenges. In mouse model of malignant glioma, we observed that a small fraction of intranasally delivered neural stem cells (NSCs) can migrate to the brain tumor site. Here, we demonstrate that hypoxic preconditioning or overexpression of CXCR4 significantly enhances the tumor-targeting ability of NSCs, but without altering their phenotype only in genetically modified NSCs. Modified NSCs deliver oncolytic virus to glioma more efficiently and extend survival of experimental animals in the context of radiotherapy. Our findings indicate that intranasal delivery of stem cell-based therapeutics could be optimized for future clinical applications, and allow for safe and repeated administration of biological therapies to brain tumors and other CNS disorders.
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
Mahua
M
Dey
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Dou
D
Yu
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Deepak
D
Kanojia
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
Gina
G
Li
Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Madina
M
Sukhanova
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Drew A
DA
Spencer
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Katatzyna C
KC
Pituch
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA.
Lingjiao
L
Zhang
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Yu
Y
Han
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Atique U
AU
Ahmed
Division of Neurosurgery, Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Karen S
KS
Aboody
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Maciej S
MS
Lesniak
The Brain Tumor Center, The University of Chicago, Chicago, IL 60637, USA; Department of Neurological Surgery, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: irinabal@northwestern.edu.
Irina V
IV
Balyasnikova
D000281:Administration, Intranasal; D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D010641:Phenotype; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D033581:Stem Cell Transplantation; D014161:Transduction, Genetic; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D015415:Biomarkers; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4