Abstract:
The search for effective treatments against glioblastoma, the most common and aggressive type of primary brain tumour, has been met with limited success over the last decade. The blood-brain barrier (BBB) continues to be a major challenge in this process by limiting the distribution of drugs to the brain. Omega-3 fatty acids have the capacity to penetrate the BBB and are essential for normal brain development and function. These fatty acids have also demonstrated anti-tumour effects against a range of experimental cancer models. These findings have led to the development of novel epoxy omega-3 fatty acid analogues that may distribute to the brain and be effective against brain tumours. A range of epoxy omega-3 fatty acid analogues reduced the cell viability of the GL261-luc2 glioma cell line in vitro. In animal studies, the daily dosing of 16-{3-[4-chloro-3- (trifluoromethyl)phenyl]ureido}hexadecanoic acid (C29) at 50 mg/kg intraperitoneally (i.p), significantly delayed growth of subcutaneous (s.c) tumours, and demonstrated a trend towards a prolonged survival. C29 treatment decreased intracranial (i.c) tumour bioluminescence (BLI), however, no survival benefit was observed. Ethyl 16-{[(4 methylphenyl)carbamoyl]amino}hexadecanoate (CUT-EE) at 50 mg/kg i.p daily, did not demonstrate activity against either s.c or i.c tumour models. A rapid and sensitive LC-MS/MS method was developed and validated for measuring epoxy omega-3 fatty acid analogues in mouse plasma, brain, s.c tumour and liver tissues. C29 exposure following a 50 mg/kg i.p dose was significantly lower in brain versus plasma and s.c tumour tissues, with a brain to plasma exposure ratio of 0.09. Accumulation of C29 in the brain was observed after a repeated dose, whereas brain accumulation with CUT-EE was seen after a single dose. CUT-EE brain concentrations increased over 24 h following administration, and surpassed plasma concentrations to demonstrate a brain to plasma exposure ratio of 124. In conclusion, preclinical results of two epoxy omega-3 fatty acid analogues herein demonstrated C29’s anti-tumour effects of against a s.c murine glioma model, and CUT-EE’s capacity to distribute and accumulate in the brain. The findings reported in this thesis support the prospect of designing further epoxy omega-3 fatty acid analogues that combine both anti-tumour and brain penetrating characteristics, and offer a promising outlook for treating brain tumours.