Towards the synthesis and delivery of a halogenated MCT1 substrate
<p>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 aggressiv...
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| מחברים אחרים: | |
| פורמט: | Thesis |
| שפה: | English |
| יצא לאור: |
2019
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| נושאים: |
| _version_ | 1826275993686376448 |
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| author | Skaripa-Koukelli, Eirini |
| author2 | Vallis, K |
| author_facet | Vallis, K Skaripa-Koukelli, Eirini |
| author_sort | Skaripa-Koukelli, Eirini |
| collection | OXFORD |
| description | <p>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.</p>
<p>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.</p>
<p>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.</p>
<p>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 (<sup>‘123</sup>I-HPLA’) was synthesised and tested for selectivity towards MCT1- expressing cells with positive outcomes.</p>
<p>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.</p>
<p>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.</p> |
| first_indexed | 2024-03-06T23:07:17Z |
| format | Thesis |
| id | oxford-uuid:644745d6-9ce1-4039-a6fa-6f46196c3c8f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:07:17Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:644745d6-9ce1-4039-a6fa-6f46196c3c8f2022-03-26T18:17:58ZTowards the synthesis and delivery of a halogenated MCT1 substrateThesishttp://purl.org/coar/resource_type/c_db06uuid:644745d6-9ce1-4039-a6fa-6f46196c3c8fDrug delivery systemstargeted radionuclide therapytumour metabolismEnglishHyrax Deposit2019Skaripa-Koukelli, EiriniVallis, KCarlisle, RSeymour, LAlexander, C<p>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.</p> <p>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.</p> <p>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.</p> <p>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 (<sup>‘123</sup>I-HPLA’) was synthesised and tested for selectivity towards MCT1- expressing cells with positive outcomes.</p> <p>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.</p> <p>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.</p> |
| spellingShingle | Drug delivery systems targeted radionuclide therapy tumour metabolism Skaripa-Koukelli, Eirini Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title | Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title_full | Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title_fullStr | Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title_full_unstemmed | Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title_short | Towards the synthesis and delivery of a halogenated MCT1 substrate |
| title_sort | towards the synthesis and delivery of a halogenated mct1 substrate |
| topic | Drug delivery systems targeted radionuclide therapy tumour metabolism |
| work_keys_str_mv | AT skaripakoukellieirini towardsthesynthesisanddeliveryofahalogenatedmct1substrate |