In situ generated biopolymers towards a reverse prodrug therapy for hard-to-treat cancers
Publication Date
July 30, 2025
Creator
Abstract
Glioblastoma (GBM) is a highly aggressive form of brain tumour with poor patient prognosis. There is, therefore, a clinical need to find novel approaches to treat the disease. Tumour treating fields (TTFields) are low-intensity, intermediate-frequency, alternating electric currents that are licensed for the treatment of GBM. While they increase patient survival as compared to the standard treatment, expensive treatment costs and small improvements in life expectancy mean there is a need to enhance the efficacy of this cancer therapy.
Cell-induced polymerisation is a potential new approach to treat cancer. It follows a ‘prodrug’ strategy, where a biocompatible monomer is chemically transformed to a polymer that can induce cell death. An alternative method instead follows a ‘reverse prodrug’ strategy, where a cytotoxic monomer induces an effect on the cells; the subsequent polymerisation then curtails this toxicity.
This thesis explores the potential to combine a conductive polymer formed by a ‘reverse prodrug’ approach with TTFields as a dual modality to induce cancer cell death.
An effective strategy for the characterisation of the polymer in two glioblastoma cell lines was first found. Solid state nuclear magnetic resonance was shown to be most suitable for identifying the presence of polypyrrole in samples that also contained cell debris. The mechanism of cell death was also investigated, with a combination of apoptotic and necrotic death observed in both cell types. Variation in the degree of cell death between cell types indicates the potential to tailor this ‘reverse prodrug’ treatment for cancer therapy.
To understand the mechanism of the ‘reverse prodrug’ polymerisation in a more complex organism, the Caenorhabditis elegans (C. elegans) in vivo model was used. Raman spectroscopy proved a valuable tool for the identification of both polymer and iron initiators in the presence of nematodes. Evidence was found that polypyrrole was formed in situ in samples containing monomer and C. elegans. This is the first time that polypyrrole has been synthesised in situ with C. elegans. The toxicity of the starting materials was also investigated, with effects on acute survival and nematode development assessed. These results showed that at concentrations less than or equal to 20 mM, pyrrole did not induce nematode death, however growth was arrested. Toxicity was also compared in two mutated C. elegans cancer models, with similar profiles observed.
To combine the cell-induced polymerisation with TTFields, a high-throughput platform capable of generating electric fields was designed. This electrode setup was then coupled with the ‘reverse prodrug’ approach, and the combination of both electrical stimulation with cell-mediated formation of polypyrrole resulted in a significant decrease in cell viability of 79% compared to the stimulation-only control. The results from this work indicate the potential to combine the two treatments in a dual approach to treat glioblastoma. By combining TTFields with inorganic nanoparticles, the efficacy of treatment in vitro was also shown to be enhanced, with metabolic activity decreased by between 12 – 18%.
As the prognosis for GBM is so poor, it is essential that novel alternative therapies are explored to better treat the disease. This thesis paves the way for further research in combining TTFields with conductive materials formed by a ‘reverse prodrug’ approach as a potential dual approach to treat cancer.
Item Type
ethesis
Thesis Type
PhD
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
80815
UoN Repository URI
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