Evaluation of liver toxicological effects induced by polyalkylcyanoacrylate nanoparticles

Abstract

Intravenous administration of drug-loaded polyalkylcyanoacrylate (PACA) nanoparticles is followed by a rapid uptake by the tissues of the reticuloendothelial system, mainly the liver. Nevertheless, it is so far unknown whether chronic administration of nanoparticles can lead to damage to the liver cells. We have studied the subacute toxicological effects of these drug carriers in a rat in vivo/ex vivo model. Nanoparticles were administered intravenously at a total dose of 200 mg/kg for 14 days (10 individual doses of 20 mg/kg). Hepatocytes were then isolated. Levels of alpha 1-acid glycoprotein secretion increased while albumin secretion decreased in hepatocytes from rats treated with PACA nanoparticles. In addition, glucose production due to the fructose metabolism was lowered. Treated rats induced a temporary increase and hyposialyation of serum alpha 1-acid glycoprotein. These effects were reversible 15 days after the treatment was concluded. Finally, the involvement of Kupffer cells and polymer degradation products was studied in vitro. Modifications of hepatocyte protein synthesis related to the treatments were only observed when direct contact between nanoparticles and hepatocytes existed. Kupffer cells and polymer degradation products did not mediate the hepatocyte response to nanoparticles in vitro. In conclusion, modifications in hepatic function after chronic administration of PACA nanoparticles have been detected by the use of very sensitive models for detecting hepatoxicity. These effects were, however, found to be reversible when the treatment was stopped.