Preparation and optimization of nilotinib loaded lipid-polymer hybrid nanoparticles for oral treatment of liver fibrosis

Abstract

In the current study, nilotinib loaded lipid polymer hybrid nanoparticles (LPHNPs) were developed to investigate their physicochemical properties and anti-fibrotic effects. Various formulations of nilotinib loaded LPHNPs were prepared using a single emulsification evaporation method and optimized through a fractional factorial design based on their physicochemical characteristics. The optimized formulation was further evaluated for the morphology and crystallinity of the formulated drug using scanning electron microscopy (SEM) and X-ray powder diffraction (XRD), respectively. Additionally, the ex-vivo intestinal permeability of nilotinib loaded LPHNPs and nilotinib suspension was assessed using the non-everted rat gut sac method. The optimized formulation exhibited a spherical shape with a mean particle size of 276.46 f 9.98 nm, a polydispersity index of 0.40 f 0.02, zeta potential of -4.57 f 0.41 mV, an encapsulation efficiency of 97.18 f 0.11 , a drug loading of 18.75 f 0.02 and a release efficacy over 72 h of 55.23 f 1.27 . XRD analysis indicated reduced drug crystallinity in the LPHNPs. In the ex-vivo intestinal permeability study, nilotinib loaded optimized LPHNPs significantly improved drug permeation through the intestinal sac, as compared to the drug suspension. An in vivo study using a rat model of bile duct ligation induced liver fibrosis also demonstrated that the oral administration of nilotinib loaded LPHNPs for two weeks significantly decreased the levels of alanine aminotransferase, aspartate transaminase, alkaline phosphatase and hydroxyproline, as compared to free nilotinib administration. Furthermore, the optimized nilotinib loaded LPHNPs improved the hepatic architecture by attenuating fibrogensis, necrosis and inflammatory cell infiltration, while also restricting bile duct hyperplasia. Notably, nilotinib loaded LPHNPs also decreased the levels of transforming growth factor beta-1(TGF-beta 1) and its receptor, TGF-beta receptor II, more effectively than free nilotinib. These results, thus, suggest that the nilotinib loaded LPHNPs have a significant potential as an oral nanomedicine for the treatment liver fibrosis.