Vandetanib-eluting beads for the treatment of liver tumours

  • Alice Hagan

    Student thesis: Doctoral Thesis


    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 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 AwardJun 2018
    Original languageEnglish
    Awarding Institution
    • University of Brighton
    SupervisorGary Phillips (Supervisor)

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