| Description |
Glioblastoma is the most common primary malignant brain tumor in adults. It is characterized by extensive invasion, an aberrant local blood brain barrier, and increased intercerebral pressure due to edema. Although there have been several advances in therapeutic strategies to treat gliomas, the current median survival for glioblastoma remains less than 2 years. A major impediment to the treatment of glioblastoma is the lack of drugs that can overcome the blood brain barrier, treat cancer cells, and not affect nearby glia and neurons. Additionally, most therapeutic strategies against cancers merely target cancer growth without affecting invasion, angiogenesis and metastasis. Glycosaminoglycans, particularly heparan sulfate and chondroitin sulfate, are responsible for regulating several pathological processes associated with the progression of glioblastoma. They interact with growth factors, chemokines, and other molecules in the extracellular matrix and within cells, to modulate aberrant cell signaling pathways that influence cancer invasion, metastasis, angiogenesis, and growth. In this dissertation, a therapeutic strategy based on glycosaminoglycan biology is designed and developed to treat gliomas and other cancers in vivo. The strategy is composed of two parts: glycosaminoglycan-based drugs (xylosides and glycosaminoglycan mimetics) and a glycosaminoglycan-based drug delivery vehicle conjugated to doxorubicin. Xylosides are small sugar monomers attached to aglycone moieties that cause cells to produce and release glycosaminoglycan chains without a coreprotein attached. It is shown that upon treatment of gliomas by xylosides, the released glycosaminoglycans dramatically reduce tumor-associated invasion and angiogenesis in vitro. As xylosides are nontoxic even at high dosages, they are an incredibly powerful means to curb tumor invasion and angiogenesis. In addition to xylosides, an optimized heparin-based drug delivery vehicle, composed of heparosan conjugated to aprotinin and doxorubicin, is developed to deliver toxic doses of doxorubicin across the blood brain barrier to gliomas. This conjugate is an exciting therapeutic not only because it can curb glioma growth, but also because it is biodegradable and easy to produce in large quantities. Based on exciting in vivo results in mice, it is expected that this strategy will show promise in future clinical studies in humans. |
