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Nano-Enabled Disulfiram for Cancer Therapy

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Nano-Enabled Disulfiram for Cancer Therapy Nano-enabled disulfiram for cancer therapy Erazuliana Abd Kadir A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy of University College London UCL School of Pharmacy 29-39 Brunswick Square London, WC1N 1AX February 2017 Declaration The thesis describes the research conducted in the UCL School of Pharmacy, University College London between 2012 and 2016 under the supervision of Professor Andreas Schätzlein. I, Erazuliana Abd Kadir, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signature : Date : 17th February 2017 ii ABSTRACT The hypothesis was that encapsulation of labile disulfiram (DS) in a high capacity nanoemulsion stabilized by quaternary ammonium palmitoyl glycol chitosan (GCPQ) could protect DS from degradation in the blood and increase its delivery to tumours. GCPQ was synthesized from glycol chitosan and characterized. GCP20Q11 polymer was chosen to be incorporated with DS in soybean oil into homogenous DS-GCP20Q11-E nanoemulsion. The nanoemulsions showed capability of oil-loading up to 50% v/v for a stable entrapment of high drug content. With increasing oil content (5 to 50%) the mean particle size increased, as did overall polydispersity (190 to 359 nm and 0.14 to 0.21, respectively). Transmission electron microscope (TEM) images showed existence of heterogeneous particles with a size below 100 nm. The drug load and colloidal stability were improved in lower oil-content formulations stored at low temperature. Formulations showed highly positive particle surface charge (51 mV at pH 4.50), proving the ionic stability of the individual particles. DS-GCP20Q11-E showed marked cytotoxicity effect against human pancreatic cancer cell line (MIAPaCa-2) with enhanced activity seen in the presence of copper (IC50 of 0.37 µM compared to 34.17 µM with the nanoemulsion treatment without copper). In vivo oral pharmacokinetic (PK) study of DS-GCP20Q11-E showed low DS level (low area under curve (AUC)) in the mouse plasma compared to control group whereas the intravenous (IV) PK showed an improved AUC value with DS half-life of 17 minutes. DS-GCP20Q11-E anticancer activity against development of human pancreatic cancer xenograft tumour in mice revealed significant prolonged survival in animals treated with IV DS-GCP20Q11- E or oral DS in soybean oil compared to control (no treatment). No toxicity or side effects were iii seen from the multiple administration of the nanoemulsion. In conclusion, DS-GCP20Q11-E nanoemulsion has the potential to be used or developed further for cancer therapeutic purposes. iv ACKNOWLEDGEMENT First and foremost, I would like to thank God for giving me the strength and dedication to finish this arduous journey. My sincere acknowledgement to my supervisors, Andreas and Ijeoma for the guidance, encouragement and support throughout these years. It was an honour for me to have been given an opportunity to learn invaluable knowledge under your supervision. A heartfelt gratitude to all of the group members in Lab 105 and 326 for all the help and care showered on me; Preethi for being there for me since day one, Sunish for the lab organisation and equipment technicalities, Ramesh and Uche for all types of help in the lab, Nick for the insightful chemistry-related guide, Funmi for the early introduction to animal work and Clemens for the companionship in the office. A big thank you also to Abdullah, Lisa, Antonio, Fionn, Ye, Lorenzo, Margarida, Xian and the rest of the people who have made the lab environment so inspiring to work in. An enormous thanks to the staffs in the school especially to Steve Coppard and all the staffs in Animal Unit for the continuous help with the animals, David McCarthy for the help with TEM imaging, Colin James for the NMR and Rob, Renu and Chris for the tremendous service with the supplies. An extended gratitude to the mates in the school for sharing the ups and downs of working and living in London – Norkasihan (KC), Atiqah, Yati, Raquel, Mina, Mandana, Mukhrish, Goh, Awis and Fauzi. My utmost gratitude is to my mother, sister and family members. Thank you for your understanding and support although we are thousands of miles away. Last but not least, a huge appreciation to the sponsors, Ministry of Higher Education Malaysia and Universiti Sains Malaysia for the precious study opportunity and generous financial support. v Table of Contents ABSTRACT .................................................................................................................... iii List of Figures ............................................................................................................... xvi List of Tables ................................................................................................................ xxi List of Abbreviations ................................................................................................. xxiii Chapter 1 ......................................................................................................................... 1 Introduction ..................................................................................................................... 1 1.1 Current cancer treatment ....................................................................................... 1 1.2 Issues with chemotherapeutic drug delivery ......................................................... 2 1.3 General issues with conventional drug delivery ................................................... 3 1.4 Nanotechnology in cancer medicine ..................................................................... 3 1.5 Strategies in cancer nanomedicine ........................................................................ 5 1.6 Chitosan-based nanocarriers ................................................................................. 7 1.6.1 Chitosan and chitosan-derived glycol chitosan ................................................ 8 1.6.2 Quaternary ammonium palmitoyl glycol chitosan (GCPQ)........................... 11 1.7 Disulfiram as a potential chemotherapeutic drug ................................................ 13 1.7.1 Anticancer properties of disulfiram ............................................................... 15 1.7.2 Disulfiram role against cancer stem cells....................................................... 22 1.8 Formulation of disulfiram with GCPQ polymers ................................................ 24 1.8.1 Polymeric micelles ......................................................................................... 27 1.8.2 Nanoemulsions ............................................................................................... 28 vi 1.9 Objectives of the study ........................................................................................ 30 Chapter 2 ....................................................................................................................... 31 Quaternary ammonium palmitoyl glycol chitosan (GCPQ) ..................................... 31 2.1 Overview ............................................................................................................. 31 2.2 Synthesis of GCPQ ............................................................................................. 32 2.2.1 Materials ......................................................................................................... 34 2.2.2 Degradation of glycol chitosan ...................................................................... 35 2.2.3 Palmitoylation of degraded GC ...................................................................... 36 2.2.4 Quaternisation of palmitoylated dGC (PGC) ................................................. 38 2.2.5 Removal of iodide .......................................................................................... 38 2.3 Characterization of GCPQ .................................................................................. 39 2.3.1 NMR spectroscopy ......................................................................................... 39 2.3.2 Molecular weight of GCPQ ........................................................................... 40 2.3.3 Materials ......................................................................................................... 42 2.3.4 Methodology .................................................................................................. 42 2.3.4.1 Level of palmitoylation and quaternisation of GCPQ ............................. 42 2.3.4.2 Gel permeation chromatography ............................................................. 43 2.3.5 Results and discussion ................................................................................... 44 2.3.5.1 Level of palmitoylation and quaternisation of GCPQ ............................. 44 2.3.5.2 Molecular weight of GCPQ ..................................................................... 48 2.4 Conclusion ........................................................................................................... 49 Chapter 3 ....................................................................................................................... 50 vii Disulfiram nanoparticle formulations......................................................................... 50 3.1 Overview ............................................................................................................. 50 3.2
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