Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma

Abstract

SummaryThe 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.

Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies

“…However, both viral [39–41] and NP [42] systems have demonstrated therapeutic benefit against glioma when delivered via the intranasal route. While there is limited literature available directly comparing the various techniques, we have demonstrated the significant survival benefit to irradiated mice after delivering oncolytic virus in NSCs cultured in hypoxic conditions in comparison to oncolytic viruses alone [5]. In the future, the scope of cross-comparison experiments should be expanded in order to determine the most efficient strategy of therapeutic delivery.…”

“…Although it has not been directly demonstrated, results may also be affected by the volume of therapeutic delivered. The fast clearance of therapeutic agents observed following IND should be taken into account when developing preclinical experiments [5,13,44]. Additionally, how stem cells utilize the olfactory and trigeminal nerve, the vasculature, and the lymphatic pathways for brain entry remains to be delineated [6,20,22,101–103].…”

“…Intranasal delivery (IND) has the advantage of bypassing the BBB entirely, and a wide range of therapeutics can reach the brain directly from the nasal passages through various mechanisms [5–7]. IND also benefits from being easily repeatable and noninvasive.…”

Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model

“…Novel stem cell-based therapeutics for malignant brain tumors are promising innovations developed in recent years, and the intranasal adaptation of this therapeutic strategy represents a leap towards clinical translation, in that non-invasive and repeated administration might dramatically reduce the barrier for patient applications and may be adaptable for out-patient services without general anesthesia or lengthy in-patient service associated with invasive surgical procedures 1,2,3,4 .…”

“…We and others have pioneered the intranasal route of stem cell delivery to brain tumors and have laid the ground work for some of the basic principles of translational research using mouse xenograft models 2,3,4 , as well as investigated the migration of stem cells in vivo via magnetic resonance imaging (MRI) reagent carriers 2 . Through these pilot explorations, we have accumulated substantial experience and gained insight on how to best construct a robust pre-clinical evaluation strategy using well-established patient-derived xenograft (PDX) mouse models of malignant glioma, while maintaining the investigative resolution to examine the nuanced mechanistic details of the sophisticated biological phenomena of the intranasal brain entry of therapeutic stem cells delivered to the nasal cavity.…”