Addressing Liver Fibrosis with Liposomes Targeted to Hepatic Stellate Cells

Abstract

Liver fibrosis is a chronic disease that results from hepatitis B and C infections, alcohol abuse or metabolic and genetic disorders. Ultimately, progression of fibrosis leads to cirrhosis, a stage of the disease characterized by failure of the normal liver functions. Currently, the treatment of liver fibrosis is mainly based on the removal of the underlying cause of the disease and liver transplantation, which is the only treatment for patients with advanced fibrosis. Hepatic stellate cells (HSC) are considered to be key players in the development of liver fibrosis. Chronically activated HSC produces large amounts of extracellular matrix and enhance fibrosis by secreting a broad spectrum of cytokines that exert pro-fibrotic actions in other cells, and in an autocrine manner perpetuate their own activation. Therefore, therapeutic interventions that inhibit activation of HSC and its pro-fibrotic activities are currently under investigation worldwide. In the present study we applied targeted liposomes as drug carriers to HSC in the fibrotic liver and explored the potential of these liposomes in antifibrotic therapies. Moreover, we investigated effects of bioactive compounds delivered by these liposomes on the progression of liver fibrosis. To our knowledge, this is the first study demonstrating that lipid-based drug carriers can be selectively delivered to HSC in the fibrotic liver. By incorporating the bioactive lipid DLPC, these liposomes can modulate different processes such as inflammation and fibrogenesis in the fibrotic liver. This dual functionality of liposomes as a drug carrier system with intrinsic biological effects may be exploited in new approaches to treat liver fibrosis.

NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

“…However the role of NOX4 in ALD with or without co-existing fibrosis has not been sufficiently evaluated. Activated HSC are the major fibrogenic cell types in the liver6789 but they were also shown to have a significant immunomodulatory role by promoting homing and activation of tissue macrophages10 via the induction of C-C chemokine receptor type 2 (CCR2) in both the bile duct ligation (BDL) and carbon tetrachloride (CCl4) models of fibrosis11. CCL2, (also known as MCP1) was also described as a key mediator of inflammation in chronic ALD12, and CCL2 levels correlated with disease severity13.…”

Targeted delivery of a novel group of site-directed transglutaminase inhibitors to the liver using liposomes: a new approach for the potential treatment of liver fibrosis

“…Contrary to the conventional view that cirrhosis is an irreversible process, recent evidence has shown that even advanced fibrosis is reversible (Friedman, 2000;Arthur, 2002;Bataller & Brenner, 2005). At present, there is no efficient pharmaceutical intervention for liver fibrosis (Adrian, 2007;Li & Wang, 2009).…”

“…The most common causes of liver fibrosis and cirrhosis include hepatitis B, hepatitis C, alcohol consumption, immune-mediated damage, genetic abnormalities, exposure to various drugs and toxic chemicals, and nonalcoholic steatohepatitis that is associated with diabetes and a metabolic syndrome (Dufour et al, 1993;Day, 2002;Adrian et al, 2007). The development of hepatic fibrosis reflects an alteration in the normally balanced processes of extracellular matrix (ECM) production and degradation (Friedman, 2000).…”

Recent developments in carbohydrate‐decorated targeted drug/gene delivery

“…26 Kamps et al first demonstrated that lipid-based drug carriers were selectively delivered to HSC in the fibrotic liver. 27,28 The liposomes from dilinoleoyl phosphatidylcholine (DLPC) showed to have antifibrotic properties, and the effects of targeted DLPC-containing liposomes on the activation of HSC and the progression of liver fibrosis were confirmed in BDL rats. Interestingly, DLPC containing liposomes strongly promoted the storage of glycogen in hepatocytes in fibrotic livers and caused accumulation of the liposomes in these cells within the fibrotic liver.…”