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Title: Vandetanib-eluting beads for the treatment of liver tumours
Author: Hagan, Alice
ISNI:       0000 0004 7427 1129
Awarding Body: University of Brighton
Current Institution: University of Brighton
Date of Award: 2018
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Drug-eluting bead trans-arterial chemo-embolisation (DEB-TACE) is a minimally invasive interventional treatment for intermediate stage hepatocellular carcinoma (HCC). Drug loaded microspheres, such as DC BeadTM (Biocompatibles UK Ltd) are selectively delivered via catheterisation of the hepatic artery into tumour vasculature. The purpose of DEB-TACE is to physically embolise tumour-feeding vessels, starving the tumour of oxygen and nutrients, whilst releasing drug in a controlled manner. Due to the reduced systemic drug exposure, toxicity is greatly reduced. Embolisation-induced ischaemia is intended to cause tumour necrosis, however surviving hypoxic cells are known to activate hypoxia inducible factor (HIF-1) which leads to the upregulation of several pro-survival and pro-angiogenic pathways. This can lead to tumour revascularisation, recurrence and poor treatment outcomes, providing a rationale for combining anti-angiogenic agents with TACE treatment. Local delivery of these agents via DEBs could provide sustained targeted therapy in combination with embolisation, reducing systemic exposure and therefore toxicity associated with these drugs. This thesis describes for the first time the loading of the DEB DC Bead and the radiopaque DC Bead LUMITM with the tyrosine kinase inhibitor vandetanib. Vandetanib selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor (EGFR), two signalling receptors involved in angiogenesis and HCC pathogenesis. Physicochemical properties of vandetanib loaded beads such as maximum loading capacity, effect on size, radiopacity and drug distribution were evaluated using various analytical techniques. Drug release was characterised using multiple in vitro models and compared with other traditional TACE drugs and in vivo pharmacokinetics. A hypoxic chamber was used to mimic embolisation induced ischaemia in order to assess the effect of hypoxia on the response of both HCC and endothelial cells to vandetanib. Finally, vandetanib loaded beads were evaluated in preclinical models of HCC. The feasibility and characteristics of loading and release of vandetanib from radiopaque DEBs were demonstrated, and the product was shown to meet specifications in terms of physical properties, handling and performance. Vandetanib suppresses proliferation and induces apoptosis in HCC cells and endothelial cells in vitro, without signs of hypoxiainduced drug resistance. Vandetanib-eluting beads have been evaluated in pre-clinical studies and found to be safe with durable drug release from beads. The data produced in this thesis has supported the transition of the product to first-in-human clinical trials.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available