Year

2019

Degree Name

Doctor of Philosophy

Department

Illawarra Health and Medical Research Institute

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with an abysmal 5-year survival rate of 9% in Australia. This rate has only marginally improved over the last 20 years, highlighting the need for improved therapeutic approaches. Chemotherapy is the current standard of care of PDAC, with a combination of nab-paclitaxel and gemcitabine one of the major first line treatments for locally advanced, non resectable and metastatic PDAC. Depending on the patients overall health (performance status), chemotherapy can be combined with radiotherapy but only moderately improves survival by approximately 13 months. The notoriously poor survival of PDAC is attributed to a number of factors including the typically advanced stage of the disease at the time of diagnosis and the rapid development of resistance to therapy. The tumour biology plays a major role in hindering chemotherapy uptake by the tumour. Desmoplasia is a characteristic of PDAC which consists of a stromal environment composed of extracellular matrix (ECM) components, activated fibroblast- and myofibroblast-like cells called pancreatic stellate cells (PSC) and inflammatory cells which contribute to the lack of response to chemotherapy by creating a tumour environment with high intratumoural tumour pressure and low vascularity. These factors combined mean therapeutic concentrations of drug often cannot be reached without intolerable toxicity to the patient.

This thesis describes a novel way of delivering currently used, but largely ineffective drugs to treat pancreatic tumours – through the development of dual drug loaded chemotherapy implants. The single-use drug delivery device is designed to be implanted intratumourally to overcome the physical barriers described above and deliver high concentrations of drugs locally, without systemic toxicity. Chapter 2 describes the optimisation of gemcitabine loading into single alginate or chitosan fibres for localised drug delivery. This involved optimisation of the wet spinning fabrication process to form the fibres with a range of gemcitabine concentrations. The fibres were characterised by scanning electron microscopy (SEM) imaging to observe surface and internal morphology, and the drug release profile assessed. The release profile of all fibre formulations displayed a large burst release, in which ~80 % of the drug was released within the first 10 h. This was then followed by efficacy assessment using two human PDAC cell lines (Mia-PaCa-2 and PANC-1) grown as 2D monolayers. Here, alginate fibres without drug showed biocompatibility, as there was no reduction in cell viability after 72 h, while gemcitabine loaded alginate fibres showed a 23-56 % reduction in viability. Conversely, wet-spun chitosan fibres without drug showed significant toxicity in all in vitro studies so was not tested in subsequent chapters. A 3D spheroid model using MCF- 7 cells was utilised as a more clinically relevant model, and over a 5 day period showed up to 52 % reduction in cell viability after treatment with gemcitabine loaded fibres.

Download

Share

COinS
 

Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.