Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.772023
Title: Liposomal delivery of glucoCEST and 2-deoxyglucoCEST reagents
Author: Story, Harriet
ISNI:       0000 0004 7660 8311
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Abstract:
Chemical Exchange Saturation Transfer (CEST) is an emerging MRI contrast mechanism that detects the presence of exchangeable protons, enabling natural sugars such as glucose to be used as contrast agents (glucoCEST). GlucoCEST offers a cheaper, safer and higher resolution alternative for the visualisation and staging of tumors than the current standard method, FDG-PET. Section 2 demonstrates that high concentrations of glucose can be encapsulated inside 1,2-dipalmitoyl-sn-glycero-3- phosphocholine (DPPC) liposomes to produce vesicular CEST contrast agents, from which the generated signal was concentration, temperature and pH dependent. The use of paramagnetic metal ions to create paraCEST agents can result in superior imaging sensitivity compared to diaCEST agents. Thus, Section 3 describes work carried out on the incorporation of lanthanide ions into liposomal glucoCEST reagents in an attempt to produce paraCEST signals. The results were largely unsuccessful due to the finding that co-solvation of glucose and lanthanide-DOTA complexes in water does not cause an significantly enhanced shift difference between the hydroxyl proton resonances and the water resonance. The in vivo CEST signal arising from the glucose analogue, 2-DG, is enhanced and prolonged in comparison to glucose due to its poor metabolism. Additionally, 2-DG is a glycolytic inhibitor and is thereby cytotoxic to cancer cells. Section 4 reports the encapsulation of 2-DG inside DPPC liposomes and the characterisation of both lipoglucose and lipo-2-DG agents when exposed to a number of variables: 0-20% PBS buffer was found to have a negligiable effect on CEST signal generation; lipo-2-DG and lipoglucose CEST signal gradually increased across the temperature range 25-37 °C; monosaccharide encapsulating DSPC liposomes were found to generate inferior signal to analogous DPPC liposomes; and smaller 2-DG liposomes appeared to give slightly greater CEST signal but this was offset by the higher internal volume and encapsulation efficiency of larger liposomes, if not corrected for. The advantages of liposomal encapsulation of monosaccharides include prolonged in vivo circulation and the potential for both passive and active tumor targeting. In Section 5, an active EGFR-targeting strategy was constructed which included the synthesis of EGFR-targeting peptides, two novel maleimide lipids and several novel short-chain PEG lipids, with the hydroxyl-capped analogue proving most promising. In addition, 2-DG was found to be a poor radiosensitiser in CRC cell lines as well as in a lung cancer cell line when a successful literature procedure was followed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.772023  DOI: Not available
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