Abstract
Drug-eluting bead trans-arterial chemo-embolisation (DEB-TACE) is a minimally invasiveinterventional treatment for intermediate stage hepatocellular carcinoma (HCC). Drug
loaded microspheres, such as DC Bead™ (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 LUMI™ 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.
| Date of Award | Jun 2018 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Gary Phillips (Supervisor) |