Diosmin-loaded solid nanoparticles as nano-antioxidant therapy for management of hepatocellular carcinoma: QbD-based optimization, in vitro and in vivo evaluation

The present work focuses on the development and evaluation of the diosmin-loaded solid lipid nanoparticles (SLNs) with the goal of improving its therapeutic efficacy in hepatic carcinoma (HCC) treatment. HCC was induced by administration of diethyl nitrosamine (DEN) intraperitoneally at a dose of 200 mg/kg in male Wistar rats. The formulation and optimization of diosmin-loaded SLNs was performed using a five-factor and two-level full factorial design. The optimized SLNs exhibited particle size of 37.48 nm, polydispersity index of 0.29 nm, entrapment efficiency of 73.46% and drug loading capacity of 9.075%. In vitro drug release analysis of SLNs performed with dialysis bag technique revealed cumulative drug release >60% in 6 h. In vitro cytotoxicity study of diosmin-SLNs on HepG2 cells showed relatively higher cytotoxicity than diosmin solution and blank SLN. After 48 h of treatment, IC₅₀ values for the diosmin-SLNs and diosmin solution were found to be 22.01 μg/mL and 33.11 μg/mL, respectively. In vivo animal study demonstrated that the hepatic DEN group rats shown hepatic nodules and antioxidant parameters that were altered by the diosmin in a dose-related fashion dramatically (p < 0.001). Diosmin-SLNs demonstrated strongest chemotherapeutic activity against DEN-induced HCC rats over diosmin solution, via the regulation of antioxidant mechanism-induced hepatic parameters. Overall, the studies indicated potential improvement in the biopharmaceutical and anticancer activity of the diosmin loaded in SLNs.