Porous 3D Silica Nanoparticle Assemblies as Post-surgical Drug Delivery Implants to Reduce Glioblastoma Recurrence

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Glioblastoma (GBM) is the most aggressive and common form of primary brain tumour in adults. GBM patients have an extremely poor median survival of < 15 months even with treatment. The occurrence of brain tumours is strongly related to age, and incidences worldwide and in the UK are rapidly rising; with a 39% rise in the UK since the 1990s to 12,071 new cases per year. The economic cost of brain tumours, including NHS treatment cost and loss of income, is ~£578 million per annum. Any technology that can improve the efficacy and safety of GBM treatment and patient outcomes will thus bear major cost savings for the UK economy. The treatment of GBM typically involves surgical tumour removal, radiotherapy, and chemotherapy. However, the aggressive tumour growth as finger-like tentacles in the brain often makes surgery ineffective, leading to unacceptably high tumour recurrence and mortality rates. As > 90% of tumour recurrences occur within 2 cm of the original tumour, the ability to prevent or delay local tumour regrowth after surgical removal of the bulk of the tumour mass will greatly improve patient outcomes. Indeed, the direct placement of a drug delivery device made from a drug-impregnated polymeric wafer (Glialdel) at the surgical site to kill residual cancer cells has modestly improved patient survival by 2 months. This approach also overcomes the usual challenge of drug delivery to the brain as it eliminates the need to transport the drug across the highly impermeable blood-brain barrier. However, the short acting nature of Glialdel has led to its small patient survival benefits, thus necessitating the development of more advanced drug delivery devices that could confer longer term drug release of more effective anticancer drugs to improve treatment outcomes.The aim of this project is to develop an implantable drug delivery technology to provide slow and sustained release of anticancer drugs in response to specific biological signals such as enzymes and chemicals after removal of the bulk of the tumour mass by neurosurgeons. This will be achieved by assembling 3D fibre-like structures from highly uniform porous silica nanoparticles. This system offers unprecedented porosity control for anticancer drugs to be loaded both inside the pores of the nanoparticles and in the spaces between the nanoparticles, thus enabling a high amount of anticancer drug to be delivered. As the pores between the nanoparticles are larger, faster initial drug release is expected, which will be followed by a slower sustained drug release from the smaller nanoparticle pores. The ability to precisely tune the interparticle pore sizes and surface area by varying the size and concentration of the nanoparticles and the inclusion of a natural polymer, hyaluronic acid, will allow the drug release to be more tightly regulated. This approach thus has the potential to provide steady long-term drug release which could improve the treatment safety and efficacy compared to other conventional local drug delivery systems. The 3D fibres will be formulated in a hydrogel to enhance their application at the brain cavity by neurosurgeons. The safety and efficacy of the 3D structures and hydrogel formulation will be studied in patient derived GBM and non-cancerous cells, which retain the native characteristics of the relevant human brain tissues.We have assembled a world-class multidisciplinary team of experts in materials chemistry, drug delivery, cancer biology, and neurosurgery to develop the drug delivery system. The complementary research expertise will ensure that the technology development is underpinned by a strong knowledge of cancer biology and clinical needs to maximise potential for technology translation and impact. The findings of this study will have wider applications for local drug delivery to other types of cancers and diseases for which the ability to control the release rates and provide long-term drug release is important.