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Title: Towards the synthesis and delivery of a halogenated MCT1 substrate
Author: Skaripa-Koukelli, Eirini
ISNI:       0000 0004 9347 7210
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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The monocarboxylate transporter 1 (MCT1) has received special attention as a potential therapeutic target in cancer thanks to its role in lactate shuttling. In breast cancer (BC), high MCT1 expression has been correlated with basal-like phenotype and a ‘triple-negative’ status, an aggressive subgroup of tumours with no identified molecular targets. In this thesis, MCT1 was targeted with a brominated pyruvate derivative, 3-bromobyruvate (3BP). 3BP is an alkylating agent known to inhibit glycolysis. Here, it was shown that 3BP is selectively toxic to cells expressing MCT1. Metabolomics, used to investigate metabolic effects, is a high-throughput, unbiased approach that requires no assumptions on possible targets. Inhibition of glyceraldehyde phosphate dehydrogenase (GADPH), an established 3BP target, was confirmed. Accumulation of pentose phosphate pathway (PPP) intermediates, inhibition of nucleotide synthesis, ATP and thiol-based antioxidant depletion were found to be profound in MCT1- expressing cells. The reactivity of 3BP towards thiols necessitates the use of a delivery system. 3BP was encapsulated in cavitation-sensitive liposomes and co-administered with lipid microbubbles (MBs) as ultrasound contrast agents (UCAs). Ultrasound locally triggers the release of the therapeutic, which was confirmed using an in vitro apparatus developed in house. With radiotherapy being one of the main modalities used in BC treatment, the next question was whether a radio-labelled therapeutic agent could be delivered via MCT1. A radio-iodinated lactate derivative (‘123I-HPLA’) was synthesised and tested for selectivity towards MCT1- expressing cells with positive outcomes. Finally, Poly(lactic-co-glycolic acid) (PLGA) MBs were investigated for the development of a novel delivery system. Clinically relevant ultrasound pressures resulted in persistent cavitation, fragmentation and accelerated monomer release from PLGA MBs. The findings of this study support the use of small halogenated carboxylic acids to selectively target MCT1 and addresses the delivery challenges associated with such compounds.
Supervisor: Vallis, Katherine ; Carlisle, Robert Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Drug delivery systems ; tumour metabolism ; targeted radionuclide therapy