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Vandetanib-Eluting Beads for the Treatment of Liver Tumours

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Vandetanib-Eluting Beads for the Treatment of Liver Tumours VANDETANIB-ELUTING BEADS FOR THE TREATMENT OF LIVER TUMOURS ALICE HAGAN A thesis submitted in partial fulfilment of the requirements for the University of Brighton for the degree of Doctor of Philosophy June 2018 ABSTRACT 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 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 hypoxia- induced 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. i ii TABLE OF CONTENTS Abstract .............................................................................................................................. i Table of Contents ............................................................................................................. iii List of figures ................................................................................................................... ix List of abbreviations and definitions .............................................................................. xiii Acknowledgements ....................................................................................................... xvii Declaration ..................................................................................................................... xix 1 Chapter One: Introduction ......................................................................................... 1 1.1 Hepatocellular Carcinoma: epidemiology and risk factors ............................... 1 1.2 The liver in health and disease .......................................................................... 1 1.2.1 Cirrhosis ........................................................................................................ 3 1.2.2 Mechanisms of hepatocarcinogenesis ........................................................... 3 1.2.3 Angiogenesis ................................................................................................. 3 1.2.4 The EGFR pathway ....................................................................................... 5 1.2.5 Physiology of liver tumours .......................................................................... 6 1.3 Treatment for intermediate unresectable HCC: TACE ..................................... 7 1.4 Novel DEB platforms: radio-opaque beads .................................................... 12 1.5 Towards development of an anti-angiogenic DEB – drug candidate selection 13 1.5.1 Vandetanib .................................................................................................. 14 1.6 The challenge of hypoxia ................................................................................ 19 1.6.1 Hypoxia related drug resistance .................................................................. 19 1.6.2 Modelling hypoxia in vitro.......................................................................... 23 1.7 Methods of pre-clinical evaluation of drug-eluting beads: in vitro and in vivo models of HCC ............................................................................................................ 23 1.7.1 Cell culture .................................................................................................. 23 iii 1.7.2 Mouse models ............................................................................................. 24 1.7.3 Woodchuck model ...................................................................................... 25 1.7.4 Rabbit VX2 model ...................................................................................... 25 1.8 Summary ......................................................................................................... 25 1.9 Aims of the thesis ............................................................................................ 26 2 Chapter Two: Physicochemical characterisation of vandetanib loaded beads ........ 29 2.1 Introduction ..................................................................................................... 29 2.1.1 Drug loading capacity and bead interactions .............................................. 30 2.1.2 Size/compressibility .................................................................................... 33 2.1.3 Radiopacity ................................................................................................. 34 2.1.4 Summary ..................................................................................................... 35 2.1.5 Aims of this chapter .................................................................................... 37 2.2 Materials and Methods .................................................................................... 37 2.2.1 Materials...................................................................................................... 37 2.2.2 Physicochemical analysis methods ............................................................. 37 2.3 Results ............................................................................................................. 43 2.3.1 Maximum vandetanib loading capacity in DC Bead and DC Bead LUMI 43 2.3.2 Effect of vandetanib loading on bead size and morphology ....................... 44 2.3.3 Bead penetration testing .............................................................................. 46 2.3.4 Vandetanib distribution within beads ......................................................... 47 2.3.5 Evaluation of drug-bead interactions using FTIR spectroscopy ................. 50 2.3.6 Radio-opacity of vandetanib loaded beads ................................................. 50 2.3.7 Suspension, handling and delivery of vandetanib loaded DC Bead LUMI 51 2.4 Discussion ....................................................................................................... 52 2.4.1 Influence of vandetanib charge states on bead properties ........................... 52 2.4.2 Prototype selection – radiopaque or non-radiopaque? ................................ 53 2.4.3 Properties of radiopaque vandetanib beads ................................................. 54 iv 2.5 Conclusion ...................................................................................................... 55 2.6 Supplementary figures .................................................................................... 56 3 Chapter Three: Evaluation and comparison of in vitro models of drug release from beads ................................................................................................................................ 59 3.1 Introduction ..................................................................................................... 59 3.1.1 Modelling drug release from DEB in vitro ................................................. 59 3.1.2 Existing models for measuring in vitro drug release from DEB ................. 61 3.1.3 Aims of this chapter .................................................................................... 64 3.2 Materials and Methods .................................................................................... 64 3.2.1 Materials .....................................................................................................
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