pH-Sensitive nanoparticles co-loaded with dimethylcurcumin and regorafenib for targeted combinational therapy of hepatocellular carcinoma

In the present work, methoxypoly(ethylene glycol)-polycaprolactone (mPEG-Hyd-PCL) and lactobionic acid-grafted poly(ethylene glycol)-polycaprolactone (LA-PEG-Hyd-PCL) mixed nanoparticles were developed for targeted delivery of dimethylcurcumin (DMC) and regorafenib (RGF) for combinational therapy of hepatocellular carcinoma. mPEG-Hyd-PCL and LA-PEG-Hyd-PCL were synthesized and characterized by 1 H nuclear magnetic resonance spectrometry, flourier transform infrared spectrometry, and gel permeation chromatography. The mixed nanoparticles of mPEG-Hyd-PCL and LA-PEG-Hyd-PCL (m/L) were prepared by a dialysis method, in which nile red was loaded to study the effect of the composition of the mixed nanoparticles on the cellular uptake. The results show that the mixed nanoparticles of mPEG-Hyd-PCL and LA-PEG-Hyd-PCL with a weight ratio of 1:0.2 (m/L(1:0.2)) exhibit the highest cellular uptake efficiency on HepG2 cells in the presence 10% fetal bovine serum. In addition, m/L(1:0.2) nanoparticles can be selectively taken up by HepG2 cells. DMC and RGF co-loaded m/L(1:0.2) nanoparticles (DMC/RGF@m/L(1:0.2)) were then prepared and evaluated regarding the in vitro drug release, cellular uptake, and in vitro antitumor effect . The results show that DMC/RGF@m/L(1:0.2) nanoparticles exhibit pH-sensitive drug release, enhanced cellular uptake amount and in vitro antitumor effect on HepG2 cells as compared to DMC/RGF@mPEG-Hyd-PCL and DMC/RGF@LA-PEG-Hyd-PCL nanoparticles. Although the in vitro antitumor effect of DMC/RGF@m/L(1:0.2) nanoparticles is still lower than DMC/RGF mixture, they might achieve selective cytotoxicity against hepatoma cells.