The use of low molecular weight heparin-pluronic nanogels to impede liver fibrosis by inhibition the TGF-β/Smad signaling pathway

Low molecular weight heparin (LH) has been reported to have anti-fibrotic and anti-cancer effects. To enhance the efficacy and minimize adverse effects of LH, a low molecular weight heparin-pluronic nanogel (LHP) was synthesized by conjugating carboxylated pluronic F127 to LH. The LHP reduced anticoagulant activity by about 33% of the innate activity. Liver fibrosis was induced by the injection of 1% dimethylnitrosamine (DMN) in rats, and LH or LHP (1000 IU/kg body weight) was treated once daily for 4 weeks. LHP administration prevented DMN-mediated liver weight loss and decreased the values of aspartate transaminase, alanine transaminase, total bilirubin, and direct bilirubin. LHP markedly reduced the fibrotic area compared to LH. Also, LHP potently inhibited mRNA or protein expression of alpha-smooth muscle actin, collagen type I, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-1 compared to LH, in DMN-induced liver fibrosis. In addition, LHP decreased the expression of transforming growth factor-beta(1) (TGF-beta(1)), p-Smad 2, and p-Smad 3, which are all important molecules of the TGF-beta/Smad signaling pathway. The results support an LHP shows anti-fibrotic effect in the liver via inhibition of the TGF-beta/Smad pathway as well as by the elimination of the extracellular matrix. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.