Abstract
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.
Original language | English (US) |
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Pages (from-to) | 471-482 |
Number of pages | 12 |
Journal | Stem cell reports |
Volume | 7 |
Issue number | 3 |
DOIs | |
State | Published - Sep 13 2016 |
Funding
This work was supported by NIH R01NS087990 (M.S.L., I.V.B.) and U01NS069997 (M.S.L.), and NIH/NRCDP K-12 award (M.D.). We thank Dr. Meijing Wu for her contributions to data analysis. We are grateful to Dr. C. David James for providing patient-derived GBM6 and GBM43 cell lines. K.S.A. is an uncompensated Board Member, Chief Scientific Officer, and shareholder of TheraBiologics.
ASJC Scopus subject areas
- Genetics
- Biochemistry
- Cell Biology
- Developmental Biology