DESCRIPTION (provided by applicant): Malignant gliomas are among the most devastating tumors, with survival only one to three years after diagnosis even with the best of treatments. Surgery and radiation therapy (followed by adjuvant chemotherapy), which form the standard practice, very often fail because of uncertainty in delineating the margin of the tumor. Moreover due to infiltrative nature of glioblastomamulteforme (GBM), it is not possible to resect 100% of tumor mass during surgery. Gene therapy promises to improve the prognosis of GBM, however, several factors including the lack of an efficient vector limit the ability of gene therapy to produce the desired success. Moreover, the vehicles for successful delivery of desired gene at desired site is still lacking. In recent years, different stem cells have been successfully employed to carry a gene to target tumor sites. The combination of gene transfer techniques with cellular transplantation is an elegant and promising approach to the delivery of therapeutic molecules to normal or neoplastic cells in the CNS. We have reported the ability of endothelial progenitor cells (EPCs), a class of hematopoietic stem cells, to migrate and incorporate into the angiogenesis of implanted glioma. EPCs have migrated actively at the periphery of the tumors when administered intravenously or locally and incorporated into angiogenesis. Detection of migration and incorporation was possible due to magnetic labeling of EPCs. These EPCs can be used as carrier as well as delivery vehicles for gene into tumors. Moreover, by magnetic labeling (using FDA approved ferumoxides and protamine sulfate);these cells can be used as cellular probes for MRI to track the movement of the cells after administration. Accessibility, easy harvesting and established techniques for genetic manipulation renders EPCs as attractive cellular vehicles when systemic gene carrier is required. In this proposed research, we aim to investigate the ability of EPCs to carry a gene to the tumor sites and use these transgenic cells as cellular probes to track the migration and incorporation in the tumors by magnetic resonance imaging (MRI). The goals of this research will be achieved by making glioma model in nude rats and magnetically labeled or unlabeled transgenic (carrying human sodium iodide symporter, hNIS) EPCs will be administered either systemically or locally, and the migration, homing and incorporation of these cells into tumor neovasculatures will be detected by MRI and nuclear medicine imaging technique (SPECT). If these cells carry and express hNIS at tumor sites (which will be detected by SPECT), it will open a new area of investigation with clinical applicability, where EPCs can be used as gene carrier or delivery vehicles. The long-term goal of this proposal is to extend the findings into clinical use by collecting stem cells from patients'peripheral blood and manipulate them as gene delivery vehicles for both systemic and local administrations, which can also be used as imaging probes for MRI.The results of this proposed project will advance the methods of diagnosis and treatment in two ways. Magnetically labeled cells will help detect the tumors using in vivo MRI by targeting active site of angiogenesis and this may help clinician to plan anti-angiogenic treatment strategy. If we are able to efficiently transfect and track the homing of these transgenic cells at the site of glioma, it will open a new way of delivering gene (for different factors) to the site of tumors using EPCs. Mixing magnetically labeled cells (for example 10% of total administered cells) with transgenic cells, MRI can also be used to confirm the migration and homing of transgenic cells at the sites of interest. Moreover, magnetically labeled transgenic cells can be delivered to a site of interest by applying external magnetic field during intra-arterial infusion.
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