Chemically produced neural progenitors loaded with ferumoxide-protamine sulfate complex for visualization of gliomas

点击翻译按钮获取中文摘要

Glioblastoma is a highly invasive tumor with a recurrence rate of 98%, which is in most cases rapidly fatal. The failure of current clinical and experimental therapies to eradicate disseminated glioma cells results in tumor recurrence and a median survival of 3–6 months. Furthermore, currently available imaging technologies are not sufficiently sensitive for detection of small tumor satellites, which are responsible for recurrence. Recent research advances have established mesenchymal stem cells (MSCs), neural stem cells (NSCs), and neural progenitor cells (NPCs) as promising therapeutic delivery vehicles for gliomas. These stem cells track down cancer cells in the tumor mass as well as migratory cancer cells into the brain parenchyma. Because of this unique ability, the use of MSCs and NSCs/NPCs as therapeutic and imaging modalities has been explored. Several recent studies demonstrated many advantages of NSCs over MSCs. Specifically, NSCs have a unique ability to suppress tumor growth in vivo, and exhibit greater and more specific tropism to gliomas. The disadvantage of NSCs is the lack of an adequate NSC source. Current alternative approaches to produce NSCs by induced pluripotent stem cell (iPSC) technologies are fraught with incalculable risks. Recently, we have been able to generate neural stem/progenitor cells from human bone marrow and adipose derived MSCs using a purely chemical approach (or small molecule approach) that has several advantages over currently known technologies. Our recent studies demonstrated that these chemically induced neural progenitors (CiNPCs) exhibited higher migratory capacity to malignant glioma D54-GM cells compared to hMSCs which was further increased by pre-exposure of these cells to D54-MG conditioned medium (GCM). Thus, CiNPCs produced by our recently developed safe, fast, reproducible, and cost-effective reprogramming approach can be efficiently used as a drug delivery vehicle for the treatment of brain tumors and/or as carriers for magnetic resonance imaging (MRI) contrast agents for visualization of gliomas. The goal of this SBIR phase I proposal is to investigate whether GCM pre-exposed and magnetically labeled CiNPCs could be utilized for visualization of intracranial D54-MG glioma cells by MRI. Phase II studies will investigate the potential use of these cells for MRI visualization of different types of gliomas. Commercial and clinically compatible research products emerging from Phase I/II work includes technology for large-scale clinical grade production of magnetically loaded CiNPCs that can be used for visualization of different gliomas by MRI. To achieve these goals the following Specific Aims are proposed for Phase I studies. Specific Aim 1 will test the hypothesis that GCM pre- exposed CiNPCs loaded with ferumoxide-protamine sulfate complex (FE-Pro) will retain their viability and tropism to D54-MG cells in vitro. Specific Aim 2 will test the hypothesis that GCM pre-exposed and FE-Pro- loaded CiNPCs will exhibit tropism to D54-MG glioma xenografts in vivo, which can be monitored by MRI.