AbstractRecent observations in cancer biology have shown increasing resistance to thymidylate synthase (TS) inhibitors such as 5-FU, particularly in colorectal cancer (CRC) patients, reducing the effectiveness of standard of care by chemotherapies. dUTPase; a nucleotide pool cleanser that has been observed to be highly expressed in CRC, so dysregulation of dUTPase makes an attractive target for potentiating an anti-cancer response. Using vibrational ball milling 4 novel molecules were synthesised, with chalcogen modifications to enable prodrug capabilites that is specific to dUTPase mediated degradation. The molecules facilitate complexation with the amphipathic cell-penetrating peptide; RALA, to produce nanoparticles (NPs) that can overcome extracellular and intracellular barriers and impact directed delivery of cargo into the nucleus of a mammalian cell. NPs have demonstrated effective anticancer activity in the HCT116 CRC cell line, meanwhile parallel studies on HT29 CRC and NCTC 929 cells, which exhibit reduced expression of dUTPase reveal that the lead candidate is significantly less effective. Indicating that the molecule is responsive to dUTPase expression and reflecting a degree of targeting and selectivity to specific cancer tissues, whilst unharming healthy tissues. In vivo studies on BALB/c SCID mice reveal no significant acute negative health impacts on mouse behaviours, nor organ damage by histology and organ safety assays. Pharmacokinetic analysis reveals RALA potentiating effective delivery and internalisation into surrounding tissues, translating the in vitro findings. Ultimately, tumour growth delay studies have shown significant inhibition of tumour growth dynamics with tumour doubling time and prolonged median survival by two weeks.
Thesis embargoed until 31 July 2027.
|Date of Award||Jul 2022|
|Sponsors||Northern Ireland Department for the Economy|
|Supervisor||Joseph Samuel Vyle (Supervisor) & Helen McCarthy (Supervisor)|
- cell penetrating peptide
- Dinucleoside Tetraphosphate
- colorectal cancer