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AL Fayez, Nojoud

University of British Columbia

Life threatening liver diseases such as cirrhosis and viral hepatitis accounts for 2 million global deaths annually. The major limitations of the current pharmacological therapies are the inability to deliver sufficient concentrations of therapeutic drugs to the diseased liver cells and the activation of undesired systemic side effects. The development of lipid-nanoparticles (LNPs) for small molecular drugs delivery has grown rapidly in the past decades. Although some were successful in targeting the liver, not so many were able to target the hepatocytes, where most liver diseases reside. To address this issue this dissertation is focused on the development of a novel hepatocyte-targeting formulation, called Phospholipid-Free Small Unilamellar Vesicles (PFSUVs), to improve the treatment of many liver diseases including liver stage malaria and viral hepatitis. The developed formulation is composed of high cholesterol content (~ 83%) and TWEEN 80, a non-ionic surfactant. The first part of this dissertation explored the effect of PFSUVs’ size on the intrahepatic distribution. We found that small size PFSUVs (60 nm) selectively target the hepatocytes, whereas larger PFSUVs with an average size of 120 nm accumulate in the Kupffer cells. The second and third parts of the dissertation explored two different hepatocyte-related disease applications. First, we examined the ability of PFSUVs to improve the treatment of liver-stage malaria by efficiently delivering primaquine to the hepatocytes and reducing its hemolytic toxicity. The second application focused on enhancing the treatment of hepatitis B virus (HBV). This was achieved by stimulating the immune system to trigger the production of endogenous interferon-α, a proinflammatory cytokine. We evaluated the efficacy of PFSUVs in significantly reducing hepatitis B surface antigen (HBsAg) in a mouse model when delivering an immunomodulatory agent to the hepatocytes. The fourth part of this thesis was to explore the mechanism behind the selectivity of PFSUVs to hepatocytes. In addition to the small size of PFSUVs, we demonstrated the effect of serum proteins, specifically apolipoproteins, on the internalization of PFSUVs into hepatocytes. This work demonstrated the importance of cell-specific targeting and the potential of PFSUVs to improve the treatment in many hepatocytes-associated diseases.

Text

2023-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81053

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/