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Title: Manufacturing steps towards standard and highly reproducible liposomes for advanced drug delivery to breast cancer cells
Author: Gkionis, Leonidas
ISNI:       0000 0005 0290 641X
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2020
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Breast cancer is the most common and lethal cancer type in women worldwide with increasing occurrence and mortality rates. Breast carcinoma, specifically, accounts for almost 25% of all cancers in women with more than 50,000 cancer cases to be diagnosed in the UK each year and 1.37 million new cases over the world. Breast tumours are characterised by heterogeneity in the molecular profile and therefore tumour progression behaviour, with predominant the triple-negative types, the progesterone receptor dependent types [PgR]), the steroid hormone receptor dependent types (oestrogen receptor [ER]), and the overexpressing human epidermal growth factor receptor-2 (HER2) positive subgroups, which account for 15–20% of cases. The development of smart therapeutic nanodrug systems targeting breast malignancies has been the subject of pharmaceutical study since the late 1980s, with liposomes to be so far the most well studied drug delivery system. Liposomes can target efficiently the breast tumours either passively by taking advantage the EPR effect or actively through receptor-mediated endocytosis. In this project, the manufacturing process of PEGDOX liposomes targeting highly metastatic breast cancer cells consists the overall aim of the study. Two different preparative methods were evaluated in order to prepare liposomes with a controlled and homogeneous size (<250 nm) that could take advantage of the Enhanced Permeability and Retention (EPR) effect. According to the fabrication process, drug(s) encapsulation efficiency was optimised, reducing any potential loss of the payload(s). The first implemented method was the conventional thin-film hydration and the alternative one was a new microfluidic approach, utilising flow chemistry in µm scale conditions. We hypothesise that the one-step microfluidic practice will enhance the control over liposomes size and chemotherapeutic drug loading, along with a facile, high throughput production of the formulations. Liposomes were designed to have theranostic features to enable the tracking of internalisation and allow quantification of the cytotoxic potency of the loaded drug(s) in cancer cells. For this purpose, various in vitro studies were performed including different cell viability assays, epifluorescence microscopy and flow cytometry analysis. The family of anthracyclines, and specifically doxorubicin, is widely proved one of the most potent and effective chemotherapeutic agents for the treatment of several breast cancer types. The implementation and evaluation of alternative antitumor agents, and especially naturally derived ones that possess a milder but sufficient pharmacological profile, was of high interest in this work as well. A set of novel synthetic alkoxy coumarin derivatives as well as a synthetic pentapeptide were tested in a panel of breast cancer cells and healthy fibroblasts for their cytotoxic activity. Among the potential candidates, the coumarin umbelliprenin and the pentapeptide showed significant antitumor efficacy at low doses and as such they were chosen for in vitro co-treatment along with doxorubicin (promising synergistic activity), as well as encapsulation in the liposomal formulations that produced by both preparative methods. Lastly, it was found, surprisingly, that umbelliprenin and two of its homologues induced significant morphological alterations over the liposomes size and shape, indicating these molecules as potential stabilizers of the lipidic bilayer.
Supervisor: Aojula, Harmesh ; Harris, Lynda ; Tirella, Annalisa Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: liposomes ; drug delivery ; microfluidics ; thin-film hydration ; breast cancer ; doxorubicin ; coumarins ; pentapeptide