EVALUATION OF LIVER TOXICOLOGICAL EFFECTS INDUCED BY POLYALKYLCYANOACRYLATE NANOPARTICLES

Intravenous administration of drug-loaded polyalkylcyanoacrylate (PACA ) nanoparticles is followed by a rapid uptake by the tissues of the re ticuloendothelial system, mainly the liver. Nevertheless, it is so far unknown whether chronic administration of nanoparticles can lead to d amage to the liver cells. We have studied the subacute toxicological e ffects of these drug carriers in a rat in vivo/ex vivo model. Nanopart icles were administered intravenously at a total dose of 200 mg/kg for 14 days (10 individual doses of 20 mg/kg). Hepatocytes were then isol ated. Levels of alpha 1-acid glycoprotein secretion increased while al bumin secretion decreased in hepatocytes from rats treated with PACA n anoparticles. In addition, glucose production due to the fructose meta bolism was lowered. Treated rats induced a temporary increase and hypo sialyation of serum alpha 1-acid glycoprotein. These effects were reve rsible 15 days after the treatment was concluded. Finally, the involve ment of Kupffer cells and poly mer degradation products was studied in vitro. Modifications of hepatocyte protein synthesis related to the t reatments were only observed when direct contact between nanoparticles and hepatocytes existed. Kupffer cells and polymer degradation produc ts did not mediate the hepatocyte response to nanoparticles in vitro. In conclusion, modifications in hepatic function after chronic adminis tration of PACA nanoparticles have been detected by the use of very se nsitive models for detecting hepatoxicity. These effects were, however , found to be reversible when the treatment was stopped. (C) 1995 Acad emic Press, Inc.