Platinum nanoclusters to tackle paediatric glioblastoma

Thesis

Pediatric glioblastoma (p-GBM) is an aggressive high-grade glioma with an incidence rate of 8.5 cases per million per year. Treatments such as surgical resection, chemotherapy, and radiation can be employed, but the disease location, blood-brain barrier (BBB) and systemic toxicity towards the immature organ make the clinical outcomes remain poor. This study designed bovine serum albumin (BSA) stabilized platinum nanoclusters (PtNCs) with diameter ~2nm to enable effective delivery to the tumour site. The size of the nanoclusters gives a high surface area to volume ratio; therefore, they have unique properties including catalytic ability to allow them to produce Reactive Oxygen Species (ROS) to achieve a therapeutic effect.

The aim of this thesis is to evaluate the anti-tumour potential and mechanism of PtNCs towards GBM cells and then compare with larger (10nm) PtNPs and cisplatin. Targetting the tumour cells and delivering via the olfactory and trigeminal nerve channels in an active manner by conjugating ankyrons (CD221) and rabies virus glycoprotein peptides (RVG29) showed that the nose to the brain (N2B) route is a promising way to bypass the BBB.

In vitro studies demonstrated that PtNCs could prevent cell migration and colony formation without causing normal control cell death. Unlike PtNPs and cisplatin, PtNCs also induced superior oxidative stress in p-GBM cells, causing the Gap 2/mitosis (G2/M) phase arrest directly in the cell cycle. Although conjugation with ankyrons and RVG peptides did not significantly enhance cellular uptake, transwell experiments confirmed that PtNCs could pass the nasal epithelium without disrupting the tight junction integrity. PtNCs could potentially be directly delivered to the olfactory region as demonstrated via a 3D-printed nasal model. These findings indicate that the PtNCs, with enhanced nasal permeability and distinct anti-cancer mechanisms, represent a promising therapeutic strategy for p-GBM and a potential alternative to conventional platinumbased chemotherapeutics.

Authors: Liu, Z

• DOI: 10.5287/ora-brpjagxyx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: paediatric glioblastoma; cancer therapy; platinum nanoclusters