Biomaterial approaches for Glioblastoma therapeutics

Glioblastoma (GBM) is one of the most aggressive malignant tumours of the brain and has a poor prognosis. The standard care of treatment of a patient diagnosed with GBM comprises total surgical resection of the tumour (if possible) followed by radiotherapy and an alkylating agent, temozolomide. However, despite the treatment, the tumour often reoccurs within or near the original region. Therefore, local delivery of therapeutics to GBM offers an advantage in targeting GBM recurrence or inoperable tumours. Other benefits of local delivery include minimising the systemic toxicity, bypassing the blood-brain barrier, and providing a tool to manipulate the microenvironments of the tumour, such as tumour hypoxia. Tumour hypoxia is associated with poor prognosis, increased aggressiveness, and treatment resistance. Chronic exposure to hypoxia triggers genetic adaptations orchestrated by hypoxia-inducible factor 1 (HIF1), which promote tumour survival and resistance. In addition, hypoxia interferes with the molecular effect of radiation, resulting in decreased radio-sensitivity by the tumour cells. In this thesis, we hypothesise that the use of nanotubes functionalised with carboxylic acid can be used to load and release doxorubicin efficiently intended for intratumoural injection for GBM. Moreover, an oxygen generation biomaterial can be used to reverse the hypoxia of GBM and enhance the radiation of GBM cells incubated in hypoxic conditions. Our first aim comprised developing delivery systems for GBM to deliver chemotherapeutics locally. Doxorubicin (a topoisomerase II inhibitor) was selected for this aim because of its marked cytotoxic effect against malignant glioma cells in vitro (Wolff et al. 1999). We were able to prepare carboxylic acid-functionalised nanotubes (NTs) made of polyethylene glycol (PEG) that could load doxorubicin with an excellent loading efficiency and release it slowly. The doxorubicin loading into the NTs was achieved via electrostatic interactions between the positively charged doxorubicin and negatively charged NTs. The degree of drug loading by NTs could be tuned by varying the degree of carboxylic acid functionalisation. Doxorubicin loaded NTs decreased GBM cell viability in a dose-dependent manner. Our second aim involved the development of an oxygen-producing system to act as a radiosensitiser. Manganese dioxide (MnO2) nanoparticles were synthesised and surface modified with polyacrylic acid (PAA) to stabilise the nanoparticles in solutions. As a result, MnO2 nanoparticles were able to oxygenate 2D and 3D spheroid models and enhance the efficacy of ionising radiation. In addition, MnO2 were able to load and release doxorubicin over a long period, which could provide a multimodal system of oxygen-production and chemotherapeutic drug delivery. In conclusion, we have synthesised an injectable drug delivery system comprised of doxorubicin-loaded PEG nanotubes for the GBM. The system was successfully able to load and release doxorubicin. Moreover, we have synthesised an oxygen generating system made of MnO2, which was able to reverse the hypoxia and enhance the irradiation of the GBM