Gomez Ramirez, Ana Paulina;
(2021)
Pre-clinical evaluation of liposomal butyrate as a novel therapy for colorectal cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The preventive role of dietary fibre in the development of colorectal cancer (CRC) is widely associated with the molecular effects of short chain fatty acids (SCFA), particularly butyrate. The therapeutic value of SCFA however is limited by various factors that can be circumvented by using nanoparticle-assisted delivery to tumours. In this thesis I present my work optimizing and characterizing a novel liposomal formulation for the encapsulation of SCFA and evaluating its therapeutic potential in pre-clinical models of CRC. In vitro, butyrate reduced cellular viability and proliferation in a variety of CRC cell lines via HDAC inhibition, while the opposite was observed in healthy colonocytes. Butyrate also altered the bioenergetic and metabolomic profiles of SW1222+Luc CRC cells. Alterations in ATP production, pantothenate and TCA cycle metabolite levels were particularly marked. Incontrast, acetate had no therapeutic effects in vitro, while in vivo liposomes encapsulating acetate (LITA) increased tumour growth rates, warning against the use of this SCFA for the treatment of CRC. In vivo, liposome-encapsulated butyrate (LITB) treatment induced a reduction in tumour growth rates and glucose uptake in subcutaneous CRC SW1222+Luc tumours, as assessed by a variety of imaging methods (BLI, 18F-FDG-PET/CT, PAI & OPT), calliper tumour volumes and histology. Assessment of the in vivo effect of combining LITB with Oxaliplatin, the gold-standard chemotherapy for the treatment of CRC, warned against this combination, as tumours were larger than those treated with oxaliplatin alone. Both in vitro and in vivo data suggested that the cell might be capable of using butyrate as a source of energy in its oxaliplatin-induced struggle for survival. However the use of LITB as a priming agent prior to oxaliplatin therapy resulted in tumours significantly smaller in volume than those treated with oxaliplatin alone, making it a promising therapeutic strategy for the treatment and prevention of CRC. This is particularly attractive given the huge therapeutic value of butyrate for the treatment of associated comorbidities that delay diagnosis and increase the risk of CRC, such as inflammatory intestinal conditions. Overall the present results support the use of butyrate, or more specifically LITB, for the prevention and treatment of CRC and urge clinical evaluation of its potential.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Pre-clinical evaluation of liposomal butyrate as a novel therapy for colorectal cancer |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10138075 |
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