Investigation on New Material for DDS : Study on the Mechanisms of Release of Mucopolysaccharide from Liver in Rats

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(1) The Michaelis constant, Km for the extended uptake of LMWFH (7000DA) was 5 times larger than that of 21 nM for HMWFH (20000Da), but the other parameters were comparable with those for HMWFH.Therefore, an incease in Km, or a decease in apparent affinity, with a decrease in molecular weight in the extended uptake may be responsible for the reportde lower hepatic uptake of low molecular weight hepanin.(2) The association of fractionated heparin with rat Kupffer cells was concentration-dependent with a dissociation constant of 3.4 nM and a maximum association capacity of 1.3 pmol/10^6 cells, suggesting the involvement of a specialized mechanism. It is also suggested that the uptake mechanism may differ from receptor-mediated endocytosis of polypeptides and be mediated by scavenger receptors.(3) Molecular weight dependency in the interaction of fractionated haparin with plasma proteins was evaluated by determining the protein binding of low molecular weight fractionated heparin (LMWFH : … More 7000Da) and high molecular weight fractionated heparin (HMWFH : 16000Da). The bound fraction of LMWFH were 0.5 and 0.8 in the presence of alpha-globulin and albumin, respectively, and were about 10 times larger than those HMWFH,0.04 and 0.1, suggesting a reduction in binding with a decrease in molecular weight. However, While the uptake of LMWFH was reduced by these porteins by extents of similar to bound fractions of LMWFH,the uptake of HMWFH was reduced by extents fare smaller than bound fractions.(4) The equilibrium binding of fractionated heparin (HMWFH : 23000Da) to Kupffer cells was concentration-dependent with the dissociation constant of 5.7 nM and the maximun binding capacity of 1.5 pmol/10^6 cells. Several ligands of scavenger receptors inhibited the binding of fractionated heparin to Kupffer cells competitively and also the intemalization of heparin, suggesting the involvement of scavenger receptors in the uptake of fractionated heparin. The scavenger receptor-mediated uptake is suggested to be ATP-independent and different from receptor-mediated and adsorptive endocytosis of polypeptides and phagocytosis, although for temperature dependency ti showed the typical characteristics of receptor-mediated endocytosis. Less