E-Thesis 67 views
Biodegradable Nanovectors for the Treatment of Advanced Ovarian Cancer / Kadie Edwards
Swansea University Author: Kadie Edwards
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...
| Published: |
Swansea, Wales, UK
2024
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| 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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| 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 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). |
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| Keywords: |
Drug delivery, advanced therapeutics, polymer, biotechnology, cancer therapy |
| College: |
Faculty of Science and Engineering |