In vivo recognition of mannosylated proteins by hepatic mannose receptors and mannan-binding protein.
In vivo recognition of mannosylated proteins by hepatic mannose receptors and serum mannan-binding protein (MBP) was investigated in mice. After intravenous administration, all three different (111)In-mannosylated proteins were taken up mainly by liver, and uptake was saturated with increasing doses. (111)In-Man-superoxide dismutases and (111)In-Man(12)- and (111)In-Man(16)-BSA had simple dose-dependent pharmacokinetic profiles, whereas other derivatives ((111)In-Man(25)-, -Man(35)-, and -Man(46)-BSA and (111)In-Man-IgGs) showed slow hepatic uptake at <1 mg/kg. Purified MBP experiments in vitro indicated that these derivatives bind to MBP in serum after injection, which interferes with their hepatic uptake. To quantitatively evaluate these recognition properties in vivo, a pharmacokinetic model-based analysis was performed for (111)In-Man-BSAs, estimating some parameters, including the Michaelis-Menten constant of the hepatic uptake and the dissociation constant of MBP, which correlate to the affinity of Man-BSAs for mannose receptors and MBP, respectively. The dissociation constant of Man-BSA and MBP decreased dramatically with increasing density of mannose, but the Michaelis-Menten constant of hepatic uptake of Man-BSA was not so sensitive to the change in density. This suggests that the in vivo recognition of MBP has a stronger cluster effect than that of mannose receptors. Differences obtained here are due to the unique arrangement of carbohydrate recognition domains on each mannose-specific lectin available for mannosylated ligand recognition.
Opanasopit
P
P
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Shirashi
K
K
Nishikawa
M
M
Yamashita
F
F
Takakura
Y
Y
Hashida
M
M
D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000097:blood*; D037222:Collectins; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D006031:Glycosylation; D007205:Indium Radioisotopes; D007700:Kinetics; D037181:Lectins, C-Type; D008099:Liver / Q000378:metabolism*; D008297:Male; D008351:Mannans / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014018:Tissue Distribution
D002352:Carrier Proteins; D037222:Collectins; D006023:Glycoproteins; D007205:Indium Radioisotopes; D037181:Lectins, C-Type; D008351:Mannans; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface