Targeting the glioblastoma micro-environment

Abstract

The thesis "Targeting the glioblastoma micro-environment" focuses on novel approaches for glioblastoma treatment and research. Glioblastoma is the most common and lethal primary brain tumor, with patients having a median survival of 14 months. Most systemic therapeutics are not effective due to the blood brain barrier, that protects the brain from toxic substances. This thesis therefore describes the investigation of a drug loaded nanoparticle-in-hydrogel delivery platform that can be implanted intracranially for the on-site delivery of a variety of therapeutics. This platform can release two drug formulations in a sequential manner and can be modified to achieve the required profile of drug release for optimal treatment outcome. The thesis further reports the consequences of local delivery for the performance of lipid nanoparticle based RNA therapeutics that were initially designed for systemic application. It appears that the biological environment, specifically its protein composition, can affect the efficacy of certain lipid nanoparticle therapeutics. This needs to be taken into account when developing these nanoparticles for local delivery. This same principle translates to an issue encountered in lipid nanoparticle research in vitro. A standard protocol of heat inactivation of sera for the cultivation of cells not only denatured unwanted proteins that can interfere with the experiments, but also hampered the efficacy of lipid nanoparticle RNA therapeutics by denaturing proteins needed for their interactions with cells. This influences cell experiments and thus introduces bias when developing new formulations. Next, a novel model for glioblastoma specific tumor associated macrophages is described and compared to often used standard macrophage models. The novel model more accurately represents the macrophages found in glioblastoma patients tumors. The final chapter gives examples on how the gathered information can be used to develop new therapies for glioblastoma.