Evaluation of hepatic antioxidant systems after intravenous administration of polymeric nanoparticles.
We have investigated the modifications of the levels of intracellular markers of the oxidative stress in hepatocytes, after single or repeated injections of poly(isobutyl cyanoacrylate) (PIBCA) and polystyrene (PS) nanoparticles. Nanoparticles were administered intravenously at single doses of 20 and 100 mg kg 1 for 14 days. Levels of reduced (GSH) and oxidized (GSSG) glutathione, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CT) and the peroxidation of membrane lipids were measured. Single and repeated administration of PIBCA and PS nanoparticles induced a transient depletion of GSH and GSSG levels, a transient inhibition of SOD activity and a slight increase in CT activity. However, GPx activity was not modified and lipid peroxidation was not observed, suggesting that hepatocytes are not strongly affected by these modifications. Since nanoparticles do not distribute in hepatocytes, oxidative species could proceed from hepatic macrophages, activated after nanoparticle phagocytosis. It is unlikely that poly(alkyl cyanoacrylate) degradation products might be responsible for the oxidative attack because non-biodegradable PS nanoparticles induced the same effect. Uptake of polymeric nanoparticles by Kupffer cells in the liver induce modifications in hepatocyte antioxidant systems, probably due to the production of radical oxygen species. However, the depletion in glutathione was not great enough to initiate hepatocyte damage, since no changes in lipid peroxidation and reversible alterations were observed. This is an important factor to be considered in the use of polymeric nanoparticles as drug carriers.
Fernández-Urrusuno
R
R
Université Paris XI, Faculté de Pharmacie, URA CNRS, Châtenay-Malabry, France.
Fattal
E
E
Féger
J
J
Couvreur
P
P
Thérond
P
P
D000818:Animals; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D003487:Cyanoacrylates / Q000008:administration & dosage / Q000494:pharmacology*; D004659:Enbucrilate; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D005979:Glutathione Peroxidase / Q000378:metabolism; D007275:Injections, Intravenous; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D018384:Oxidative Stress; D011108:Polymers / Q000008:administration & dosage / Q000494:pharmacology*; D011137:Polystyrenes / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D001672:Biocompatible Materials; D015415:Biomarkers; D003487:Cyanoacrylates; D008563:Membrane Lipids; D011108:Polymers; D011137:Polystyrenes; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D004659:Enbucrilate; D005978:Glutathione; D019803:Glutathione Disulfide