A novel nanoparticle therapy for glioblastoma

Abstract

Glioblastoma (GBM) is a malignant brain tumour with a median overall survival of 15 months, despite best management of surgical resection, radiation therapy (RT) and chemotherapy with temozolomide (TMZ). This outlook has not changed in the last decade. Nanoparticle (NP) therapy presents an exciting novel consideration due to its ability to be formulated and target the brain. This thesis describes the evaluation of rare earth oxide (REO) NP therapies as potential treatment for GBM given the chemical properties of rare earth elements (REEs) have been shown to exert anti-cancer effects. In characterising and testing a series of four different REO NPs, it was shown that this novel NP therapy can penetrate into the GBM cell, and that it has potential to not only be cytotoxic to both immortalised and patient-derived GBM cell lines, but also augment the therapeutic effects of RT and TMZ as well. In particular, REO La2O3 was found to be the most cytotoxic REO NP tested, and further investigation into determining mechanisms of effect was pursued. The cause of cell death by La2O3 was found to be multifaceted. Involvement of both intrinsic and extrinsic apoptosis pathways was demonstrated, as well as pathways involving direct DNA damage and autophagy. Interaction with adjuvant RT and TMZ was also shown to occur via reactive oxygen species (ROS) and alteration in mitochondrial apoptosis balance respectively. Finally, the biocompatibility and biodistribution of La2O3 NP therapy was evaluated in a balb/c nude mouse model. It was observed that not only does the NP reach the brain, it also behaves quite similarly to other reported non-REO NP therapies in terms of biodistribution. There were no short- or long-term adverse events observed with the designed therapeutic regimen. Concurrent adjuvant RT and TMZ did not affect the compatibility or distribution of the NP. In summary, this thesis describes the initial investigation of a novel REO NP therapy that has shown basic promise to improve GBM management and prognosis. Its anti-GBM effects have been demonstrated and rationalised in a number of GBM cell lines, as well as its shown biocompatibility and biodistribution in a biological system. Collectively, these findings justify future GBM xenograft survival studies to elucidate the transfer from bench to bedside of this novel therapy.