Brookes, Alice
(2023)
Delivery of cannabinoids to specific anatomical regions of the brain following oral administration to reach the site of action for glioblastoma multiforme and multiple sclerosis.
PhD thesis, University of Nottingham.
Abstract
Lipid-based formulations are commonly used to improve the oral bioavailability of poorly soluble therapeutics. More recently, these types of formulations have also been explored more to alter delivery to the brain. Certain fatty acids have been reported to increase the permeability of the protective blood-brain barrier (BBB) in a reversible manner following intravascular (i.v.) administration. However, the effect of fatty acids including oleic, linoleic and myristic acids on the BBB has not been explored following oral administration. The work in this thesis explored the delivery of cannabinoids to their site of action within the brain (for example, the frontal lobe for the treatment of glioblastoma multiforme (GBM), or the temporal lobe for treatment of epilepsy) following oral administration in lipid-based formulations. The cannabinoid cannabidiol (CBD)
and a fluorinated derivative of CBD, 4’-fluoro-cannabidiol (4’-F-CBD) were studied, with the hypothesis that 4’-F-CBD would exhibit similar pharmacokinetic (PK) properties to CBD but demonstrate higher delivery to the brain due to the addition of fluorine. The work herein began by exploring the anti-cancer properties of the cannabinoids against the aggressive brain cancer, GBM. Both CBD and 4’-F-CBD were shown to inhibit GBM cell growth and overcome two major resistance mechanisms to the standard treatment of GBM with temozolomide (TMZ). The cannabinoids also demonstrated a synergistic response with imidazotetrazine compounds (TMZ and analogue, T25), where high synergy was observed when cells were exposed to a combination of 4’-FCBD with T25. Preliminary studies investigated the mechanism of anti-cancer activity of CBD, indicating that pathways including DNA-methylation are involved for the first time.
A hypothesis throughout this work was that oral administration of cannabinoids in a lipid-based formulation would increase delivery across the BBB, compared to a lipid-free formulation. This was studied in detail for CBD, with three different lipid-based formulations. Despite reports in the literature of fatty acids improving permeability across the BBB, the lipid-free formulation resulted in the highest delivery of CBD to the whole brain. However, when the individual anatomical brain regions were studied, significant differences in delivery profiles were observed. Administration in the lipid-based sesame oil formulation resulted in the highest exposure of the rostral anatomical regions of the brain to CBD, suggesting that the high oleic acid content of the sesame oil could have contributed to increased delivery of CBD to these regions. On the other hand, the lipid-free formulation resulted in high delivery to the caudal regions of the brain. High delivery of CBD to common locations of GBM tumours was observed following oral administration, demonstrating potential of the application of orally administered CBD to treat GBM.
Finally, the in vivo PK and biodistribution of 4’-F-CBD are reported for the first time. It was hypothesised that 4’-F CBD would behave similarly to CBD in most cases, but due to the addition of the fluorine atom, higher delivery to the brain could be expected. Additionally, previously reported high potency of 4’-F-CBD in in vivo behavioural assays, compared to CBD, suggests a potential difference in the biodistribution of the cannabinoid. The PK of 4’-F-CBD following oral administration was similar to that of CBD in both lipid-free and lipid-based formulations. However, study of the biodistribution indicated that the brain was exposed to higher levels of 4’-F-CBD than CBD, supporting the hypothesis that fluorination of CBD has increased the delivery to the brain. The detailed biodistribution of 4’-F-CBD to anatomical brain regions and other tissues is reported for the first time to the best of our knowledge, which is essential for the physiological based PK (PBPK) modelling of 4’-F-CBD, and its potential future applications.
Overall, this thesis demonstrates that the systemic biodistribution of cannabinoids following oral administration differs with the oral formulation. With the example of the anti-cancer application of cannabinoids, this thesis highlights the necessity to investigate the delivery to the specific anatomical brain regions of interest.
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