Pharmacologic modulation of nasal epithelium augments neural stem cell targeting of glioblastoma

Abstract

Glioblastoma (GBM) remains the most lethal and untreatable central nervous system malignancy. The challenges to devise novel and effective anti-tumor therapies include difficulty in locating the precise tumor border for complete surgical resection, and rapid regrowth of residual tumor tissue after standard treatment. Repeatable and non-invasive intranasal application of neural stem cells (NSCs) was recently shown to enable clinically relevant delivery of therapy to tumors. Treatment with chemotactic NSCs demonstrated significant survival benefits when coupled with radiation and oncolytic virotherapy in preclinical models of GBM. In order to further augment the clinical applicability of this novel therapeutic platform, we postulate that the FDA-approved compound, methimazole (MT), can be safely utilized to delay the nasal clearance and improve the ability of NSCs to penetrate the olfactory epithelium for robust in vivo brain tumor targeting and therapeutic actions. METHODS : To examine the role of reversible reduction of the olfactory epithelial barrier in non-invasive intranasal delivery, we explored the unique pharmacologic effect of MT at a single dosage regimen. In our proof-of-concept studies, quantitative magnetic resonance imaging (MRI), immunocytochemistry, and survival analysis were performed on glioma-bearing mice treated with a single dose of MT prior to intranasal anti-GBM therapy using an oncolytic virus (OV)-loaded NSCs. RESULTS: Based on histology and in vivo imaging, we found that disrupting the olfactory epithelium with MT effectively delays clearance and allows NSCs to persist in the nasal cavity for at least 24 h. MT pretreatment amplified the migration of NSCs to the tumor. The therapeutic advantage of this enhancement was quantitatively validated by tissue analysis and MRI tracking of NSCs loaded with superparamagnetic iron oxide nanoparticles (SPIOs) in live animals. Moreover, we observed significant survival benefits in GBM-bearing mice treated with intranasal delivery of oncolytic virus-loaded NSCs following MT injection. Conclusion: Our work identified a novel pharmacologic strategy to accelerate the clinical application of the non-invasive NSCs-based therapeutic platform to tackle aggressive brain tumors.

Neural Stem Cells Secreting Bispecific T Cell Engager to Induce Selective Anti-Glioma Activity

“…For this study, we modified immortalized NSCs (NCT03072134) for BiTE LLON Iron-labeled NSC LLON were followed by magnetic resonance imaging (MRI) for five days after injection into the hemisphere contralateral to tumor-bearing brain of animal subjects, as previously described [56]. T2* weighted MRI signal showed NSC LLON accumulation in the tumor-bearing hemisphere that reached maximum level at 24h after injection ( Fig 5C).…”

MSCs Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma

“…Tumor visualization using MRI was done according to a previously described protocol 22 . Detailed information on BLI can be found in supplemental materials.…”

“…Mice were treated with methimazole (50 mg/kg body weight) 2 days before IN-MSC delivery as previously described 22 . Detailed infromations can be found in supplemental materials…”

“…MSCs can cross the BBB and reach brain tumor tissue following systemic administration. Intranasal delivery (IND) is an alternative route of therapy-carrying stem cells administration that has shown effectiveness in preclinical studies for treating neurological disorders including multiple sclerosis, viral brain infections, Parkinson's disease, ischemic brain injury, and glioblastoma [18][19][20][21][22] .…”

“…We previously showed that oncolytic virotherapy, as administered locally to the tumor site or by IND using stem cell carriers, is an effective treatment when tested against models of glioblastoma. Stem cells are capable of delivering therapeutic cargos to distant parts of the brain 14,[22][23][24][28][29][30][31][32] .…”