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Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer / Kadie Edwards

Swansea University Author: Kadie Edwards

  • E-Thesis – open access under embargo until: 22nd January 2029

DOI (Published version): 10.23889/SUthesis.66104

Abstract

Ovarian cancer (OC), the most lethal gynaecological malignancy, has the fourth highest mortality rate of cancers in women. Non-specific symptoms minimise early diagnosis and late-stage disease has limited therapeutic options. Nanomedicine offers promise to improve cancer therapy by removing administ...

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Published: Swansea, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Francis, Lewis
URI: https://cronfa.swan.ac.uk/Record/cronfa66104
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first_indexed 2024-04-20T13:22:29Z
last_indexed 2024-04-20T13:22:29Z
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spelling v2 66104 2024-04-20 Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer 76d053c090d5064ae9558888f7985e92 0000-0002-1359-0359 Kadie Edwards Kadie Edwards true false 2024-04-20 BMS Ovarian cancer (OC), the most lethal gynaecological malignancy, has the fourth highest mortality rate of cancers in women. Non-specific symptoms minimise early diagnosis and late-stage disease has limited therapeutic options. Nanomedicine offers promise to improve cancer therapy by removing administration difficulties, bypassing premature drug metabolism, enhancing in vivo stability, prevent systemic exposure of the drug thus minimising side effects and enhancing drug accumulation in the tumour. Polymer nanoparticles (NP) were identified as a non-expensive and flexible alternative to clinical standard liposomes. Polyethylene Glycol-co-block-Poly(trimethylene carbonate) (PEG-pTMC) is a biodegradable and resorbable co-block polymer that can form particles in a 10 minutes when processed via direct hydration. The aims set out in this research were to develop several polymeric NPs that can be utilised to improve OC treatment by enhancing drug pharmacology or increasing concentration of drug intracellularly. Simultaneously, this work developed an advanced in vitro pipeline that can be used to evaluate biocompatibility new nanomedicines. This thesis encompasses the synthesis of a library of polymers for use as NPs including full characterisation as bulk and nanomaterials (chapter 2), biocompatibility and performance of empty NPs (chapter 3), evaluation of nanoformulation cisplatin versus free agent in vitro and in vivo (chapter 4) and finally assesses the capacity of the NP to encapsulate alternative payloads including targeted therapeutics (chapter 5). This work demonstrated the biocompatibility of PEG-pTMC NPs and identified three lead candidates. NPs demonstrated excellent biodistribution profiles in both intravenous and intraperitoneal administration, evidenced by minimal systemic exposure with high tumour and peritoneal accumulation (IP only). Three antineoplastic agents (cisplatin, gefitinib and HDACi2) with varying degrees of success in OC were encapsulated. Nanoformulations were compared to the free drug variant across several metrics (cytotoxicity, invasive potential, and tumour reduction – cisplatin only) and nanoformulations consistently enhanced therapeutic profiles over the free drug(s). E-Thesis Swansea, Wales, UK Drug delivery, advanced therapeutics, polymer, biotechnology, cancer therapy 22 1 2024 2024-01-22 10.23889/SUthesis.66104 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Francis, Lewis Doctoral Ph.D KESS 2 with Tenovus Cancer Charity 2024-04-20T14:55:10.0789121 2024-04-20T14:20:16.7479786 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Kadie Edwards 0000-0002-1359-0359 1 Under embargo Under embargo 2024-04-20T14:47:31.5330659 Output 14535082 application/pdf E-Thesis – open access true 2029-01-22T00:00:00.0000000 Copyright: The author, Kadie E. Edwards, 2024. true eng
title Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
spellingShingle Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
Kadie Edwards
title_short Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
title_full Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
title_fullStr Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
title_full_unstemmed Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
title_sort Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer
author_id_str_mv 76d053c090d5064ae9558888f7985e92
author_id_fullname_str_mv 76d053c090d5064ae9558888f7985e92_***_Kadie Edwards
author Kadie Edwards
author2 Kadie Edwards
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUthesis.66104
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 0
active_str 0
description Ovarian cancer (OC), the most lethal gynaecological malignancy, has the fourth highest mortality rate of cancers in women. Non-specific symptoms minimise early diagnosis and late-stage disease has limited therapeutic options. Nanomedicine offers promise to improve cancer therapy by removing administration difficulties, bypassing premature drug metabolism, enhancing in vivo stability, prevent systemic exposure of the drug thus minimising side effects and enhancing drug accumulation in the tumour. Polymer nanoparticles (NP) were identified as a non-expensive and flexible alternative to clinical standard liposomes. Polyethylene Glycol-co-block-Poly(trimethylene carbonate) (PEG-pTMC) is a biodegradable and resorbable co-block polymer that can form particles in a 10 minutes when processed via direct hydration. The aims set out in this research were to develop several polymeric NPs that can be utilised to improve OC treatment by enhancing drug pharmacology or increasing concentration of drug intracellularly. Simultaneously, this work developed an advanced in vitro pipeline that can be used to evaluate biocompatibility new nanomedicines. This thesis encompasses the synthesis of a library of polymers for use as NPs including full characterisation as bulk and nanomaterials (chapter 2), biocompatibility and performance of empty NPs (chapter 3), evaluation of nanoformulation cisplatin versus free agent in vitro and in vivo (chapter 4) and finally assesses the capacity of the NP to encapsulate alternative payloads including targeted therapeutics (chapter 5). This work demonstrated the biocompatibility of PEG-pTMC NPs and identified three lead candidates. NPs demonstrated excellent biodistribution profiles in both intravenous and intraperitoneal administration, evidenced by minimal systemic exposure with high tumour and peritoneal accumulation (IP only). Three antineoplastic agents (cisplatin, gefitinib and HDACi2) with varying degrees of success in OC were encapsulated. Nanoformulations were compared to the free drug variant across several metrics (cytotoxicity, invasive potential, and tumour reduction – cisplatin only) and nanoformulations consistently enhanced therapeutic profiles over the free drug(s).
published_date 2024-01-22T14:55:06Z
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score 11.012678

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