Preparation and evaluation of hepatic stellate cell selective, surface conjugated, peroxisome proliferator-activated receptor-gamma ligand loaded liposomes

Abstract

Hepatic stellate cells (HSCs) activation leads to major fibrogenic response in liver fibrosis. Selective localization of drug to HSCs can provide effective antifibrotic therapy. Thus, objectives of study were to prepare peroxisome proliferator-activated receptor-γ ligand (rosiglitazone) loaded mannose 6-phosphate modified human serum albumin (M6P-HSA) conjugated liposomes and evaluate pharmacokinetically and pharmacodynamically in rats for application of findings of studies in development of suitable and relevant product for treatment of liver fibrosis. The HSA was derivatized with mannose 6-phosphate and then coupled to optimized liposomes. Drug distribution in liver and other tissues after intravenous administration in carbon tetrachloride-induced liver fibrosis model rats was studied. Histopathological examination, estimation of biochemical markers, and grading of liver fibrosis was performed to evaluate pharmacodynamic efficacy of prepared formulation. The M6P-HSA conjugation to liposomes enhanced rosiglitazone liver uptake significantly (2.61 folds) and disappeared from systemic circulation at double rate. Favorable pharmacokinetics resulted in improved histopathological morphology, biochemical markers level, and decreased fibrosis grade. Hence, critical scrutiny of results suggested preferential and enhanced drug localization in pathogenic cells of liver providing a thinking which may result in development of product that can provide cure or at least prevention to this progressive disease necessitating liver transplant.