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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Ferguson, Elaine Lesley
Languages: English
Types: Doctoral thesis
Subjects: RC0254, RM

Classified by OpenAIRE into

mesheuropmc: lipids (amino acids, peptides, and proteins), fungi
Increasingly sophisticated new treatments such as trastuzumab (Herceptin ) and Bevacizumab (Avastin ) have contributed to reduced mortality from breast cancer over recent years, nevertheless 40--60 % of those affected still die from metastatic disease. Thus there remains an urgent need for novel therapies for breast cancer. As PLA2 (crotoxin) has proven anticancer activity but its use is limited by non-specific toxicity, and polymer-drug and polymer-protein conjugates are finding growing use as anticancer agents, the aim of this thesis was to explore the potential of polymer-PLA2 conjugates as a new treatment for breast cancer. Polymer conjugation has previously been shown to reduce systemic toxicity of proteins, prolong their plasma half-life and promote tumour-specific targeting by the enhanced permeability and retention (EPR) effect. First, the synthesis and characterisation methods were optimised using trypsin as a model. After these studies highlighted dextrin as the best polymer for conjugation, dextrin-PLA2 (Apis mellifera venom) conjugates were prepared. Dextrin was chosen for conjugation as it can be used to mask protein activity in the protein masked-unmasked polymer therapy (PUMPT) concept. Such conjugates retained 36 % enzyme activity compared to free PLA2, and moreover, unmasking by a-amylase degradation of dextrin regenerated full enzyme activity. However, while free PLA2 was found to be very haemolytic, dextrin-PLA2 displayed no haemolytic activity, and unmasking by a-amylase degradation of dextrin did not reinstate this activity. The conjugate displayed significant toxicity towards several tumour cell lines, including human breast cancer. Indirect evidence that epidermal growth factor receptor (EGFR) status and tyrosine kinase activity of the receptor influences PLA2-induced anti-proliferative activity were shown. Uptake studies have revealed that conjugation of dextrin to PLA2 reduces non-specific binding to breast cancer cells. In a further study, dextrin-PLA2's ability to burst DaunoXome using the polymer-enzyme liposome therapy (PELT) concept was assessed. Here, it was seen that the conjugate released liposomally encapsulated drug and the combination caused enhanced cytotoxicity in MCF-7 cells. These studies confirm the potential of dextrin-PLA2 as a novel anticancer agent and/or as trigger for liposomal drug release and highlight the feasibility of developing a candidate for further in vivo pharmacokinetic and activity studies.
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