Investigating the Use of Protein and Liposomal Therapeutics for the Treatment of Glioblastoma

Glioblastoma, the most aggressive form of primary brain tumors, has disappointly few treatment options, leading to a dismal prognosis for patients. While there are many traditional small molecule drugs that are effective against glioblastoma cell lines in vitro, the vast majority of these drugs are ineffective in vivo, owing to poor delivery of these drugs across the blood brain barrier into the brain tumor. This dissertation presents a series of studies into drug delivery to the brain, with a specific emphasis on delivery to brain tumors.Chapter 3 of this thesis explores the use of yeast cytosine deaminase in an enzyme prodrug therapy paradigm. In this study, an active enzyme, yCD was delivered directly to the tumor by convection-enhanced delivery, and the prodrug, 5-fluorocytosine was delivered orally. While our efficacy studies did show that this treatment regimen was able to statistically enhance survival time, a rapid clearance of the yCD protein limits the utility of this approach.Chapters 4 and 5 of this thesis explore the use of liposomally formulated drugs to treat GBM. Liposomes are small vesicles with phospholipid bilayers that can carry drugs either within the bilayer, or within the aqueous core of the liposomes. In this thesis, we explored the use of liposomes loaded with topotecan, a DNA topoisomerase I inhibitor. Chapter 3 addressed the systemic administration of liposomal topotecan, and found that this route of delivery offered substantial efficacy in multiple models of GBM. Chapter 4 attempted to increase the specificity of liposomal topotecan by attaching an antibody against the epidermal growth factor receptor (EGFR) to the liposome surface. When we delivered these targeted liposomes by CED, we saw a significant increase in survival in two mouse models of GBM. While encouraging, the invasive nature of CED will likely limit the use of this therapeutic in the clinic. In total, these studies highlight the potential utility of two popular themes in drug delivery: the use of protein-based therapeutics as well as nanoscale drug carriers, and offers insight into the future of GBM treatment