Design, synthesis and biological evaluation of novel lipid-based nanoparticle delivery system for metabolic re-engineering

Abstract

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.