Sorafenib nanocrystals enhance bioavailability and overcome multidrug resistance in liver cancer cells: an approach based on P-gp inhibition strategy

Abstract

This research aimed to improve the oral bioavailability of Sorafenib (SF) and overcome multidrug resistance in hepatocellular carcinoma cells based on P-glycoprotein (P-gp) inhibition strategy. Four nanocrystal formulations (F1–F4) were developed using Labrasol® (LB) or Gelucire® (GL) as stabilizers as well as P-gp inhibitors. The prepared SF nanocrystal (SF-NC) formulations were characterized in vitro and in vivo. The results of in vitro studies showed that LB-based nanocrystals (F2) prepared using 0.02% LB, significantly reduced the crystal size and improved the aqueous saturation solubility of SF compared to the GL-based nanocrystals. Crystal morphology analysis of SF-NC (F2) revealed a uniform arrangement of nanosized crystals with significantly smaller particle size compared to plain SF. Furthermore, in vitro cytotoxicity studies showed that LB had no significant effects on cell viability of MDR-HepG2 and SF-resistant Huh-7 cells and can be considered safe in the in vivo environment at concentrations more than 10 times its corresponding concentration in SF-NC. However, LB-stabilized SF-NC significantly reduced IC₅₀ values in MDR-HepG2 and SF-resistant Huh-7 cells compared to plain SF. In vivo absorption studies revealed that SF-NC significantly increased the rate and extent of absorption with a 1.27-fold increase in relative bioavailability. The developed SF-NC stabilized by LB as a P-gp inhibitor is expected to be a promising approach to improve oral bioavailability and restore SF's activity against multidrug-resistant hepatocellular carcinoma cells.