Dietary supplementation with fibre has been shown to ameliorate features of the metabolic
syndrome and inhibit malignant growth in certain types of cancer. These effects have been
linked to short-chain fatty acids (SCFA), mostly acetate. However, the ubiquitous role of
SCFAs in metabolism, combined with a short tissue half-life and the non-targeted nature of
oral and peripheral administrations make achieving phenotypically relevant levels of SCFA
by standard delivery techniques challenging and limit their therapeutic potential. Liposomal
encapsulation of a therapeutic agent overcomes these issues by protecting against
degradation, increasing circulation time and passively targeting both the liver and tumour
tissue.
In this research project, I have designed a bifunctional liposome formulation to transport
SCFA, monitored their distribution and uptake utilising visualisation by MRI, PET/CT and
fluorescence microscopy. These bifunctional liposomes were useful for effectively
encapsulating small molecules within their aqueous core, which in this case was acetate,
and capable of acetate delivery into cells while also being amenable to cellular imaging. I
have shown that preferential delivery of liposome encapsulated acetate (LITA) nanoparticles
to key sites of metabolic control provide beneficial therapeutic effects in animal models of
both obesity and cancer. Chronic administration of LITA nanoparticles in an obeseogenic
model led to a significant reduction in adiposity, intrahepatocellular lipid, inflammatory tone
and genetic indication of a decrease fatty acid synthesis in the liver. Application of LITA in a
murine xenograft model caused an inhibition of tumour growth in three colorectal cancer cell
lines: HT-29, HCT116 p53+/+ and HCT116 p53-/-. The mechanisms for these two outcomes
are not fully defined; however cellular energy homeostasis of both scenarios was restored.
These results indicate that LITA nanoparticles can be used to improve multiple metabolic
pathways, in vivo.