Intravascular Delivery of Neural Stem Cell Lines to Target Intracranial and Extracranial Tumors of Neural and Non-Neural Origin

Abstract

The remarkable migratory and tumor-tropic capacities of neural stem cells (NSCs and/or neuroprogenitor cells) represent a potentially powerful approach to the treatment of invasive brain tumors, such as malignant gliomas. We have previously shown that whether implanted directly into or at distant sites from an experimental intracranial glioma, NSCs distributed efficiently throughout the main tumor mass and also tracked advancing tumor cells, while stably expressing a reporter transgene. As therapeutic proof-of-concept, NSCs genetically modified to produce the prodrug activating enzyme cytosine deaminase (CD), effected an 80% reduction in the resultant tumor mass, when tumor animals were treated with the systemic prodrug, 5-fluorocytosine. We now extend our findings of the tumor-tropic properties of NSCs (using a well-characterized, clonal NSC line C17.2), by investigating their capacity to target both intracranial and extracranial tumors, when administered into the peripheral vasculature. We furthermore demonstrate their capacity to target extracranial non-neural tumors such as prostate cancer and malignant melanoma. Well-characterized NSC lines (lacZ and/or CD-positive) were injected into the tail vein of adult nude mice with established experimental intracranial and/or subcutaneous flank tumors of neural and non-neural origin. The time course and distribution of NSCs within the tumor and internal organs was assessed in various models. Resulting data suggest that NSCs can localize to various tumor sites when injected via the peripheral vasculature, with little accumulation in normal tissues. Our findings suggest the novel use of intravascularly administered NSCs as an effective delivery vehicle to target and disseminate therapeutic agents to invasive tumors of neural and nonneural origin, both within and outside of the brain.

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…Tumor-tropic NSCs have also been observed in peripheral malignancies apart from those primary brain malignancies. It is still challenging to understand the fate of NSCs in brain lesions [35]. In certain pathologies, such as in stroke lesions, transplanted cells appear to form astrocytes and neurons [36].…”

Development of human umbilical cord matrix stem cell-based gene therapy for experimental lung tumors

“…11,12 Moreover, they have been engineered to secrete antitumor proteins, such as interferon beta (IFN-b), into the tumor microenvironment with favorable therapeutic effects in rodent animal models. [11][12][13][14][15] In these cases, millions of stem cells have been transplanted systemically. However, similar approaches in humans will likely require an order of magnitude more cells to achieve a comparable effect.…”

Viruses, gene therapy and stem cells for the treatment of human glioma

“…These findings suggested that intravascularly administered NSCs may be an effective delivery vehicle to target invasive tumors of neural and non-neural origin, both within and outside the brain. 78 In general, systemic adenoviral delivery into tumors is inefficient because of liver sequestration of intravenously administered virus. Delivery of a CRAd by human MSCs was 46-fold more efficient than injection of CRAd alone indicating that human MSC migrate and deliver CRAd to distant glioma cells.…”