Artikel
Non-invasive intranasal application of neural stem cells to target intracerebral glioblastoma
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Veröffentlicht: | 16. September 2010 |
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Gliederung
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Objective: Neural stem cells (NSC) display inherent tumor-tropic properties that can be exploited for targeted delivery of therapeutic genes to invasive glioma cells. Optimized transplantation efficiency is essential for developing effective NSC-based glioma therapies. Current strategies aim to deliver genetically-modified NSC by direct intracerebral or intracavitary application immediately after glioma resection. However, from clinical experience in other neurological disorders it is well known that effective intracerebral delivery of cells is hampered by an extremely low transplantation efficiency when injected directly into the brain parenchyma. Recently, intranasal delivery has been demonstrated as a noninvasive and convenient method to rapidly deliver drugs to the CNS, bypassing the blood-brain-barrier and minimizing systemic exposure.
Methods: In order to determine the feasibility of intranasally applied neural stem cells to target intracerebrally growing brain tumors we used the orthotopic U87 and G55 human glioblastoma models in nude mice (n=10). A cell suspension of 3x105 eGFP-expressing murine neural stem cells/mouse were applied as nose drops to the nostrils. Seven days after intranasal application the brain and internal organs were harvested and immunohistological analyses were performed to assess the distribution and tumor tropism of eGFP-positive NSC.
Results: Seven days after intranasal delivery of NSC we found the vast majority of GFP-positive cells closely surrounding the intracerebrally growing glioma xenografts and enriching within the tumor mass. Even small satellite tumors distant from the main tumor mass were targeted by NSC. Quantification revealed up to 421 NSC/mm2 within the tumors and up to 907 NSC/mm2 in the immediate tumor/brain parenchyma border zone. Some GFP-positive cells were found in the olfactory bulb and in deeper brain structures suggesting that the olfactory and trigeminal pathways were utilized to enter the intracerebral compartment.
Conclusions: Here, we demonstrate proof-of-concept that the non-invasive intranasal application of neural stem cells as nose drops allows highly motile NSC to enter the brain and displays a targeted migration of NSC towards intracerebral glioma. Our data suggests that the intranasal application of cells has the potential to serve as a simple and non-invasive alternative delivery method during a complex intracerebrebral disease process.