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Am J Physiol Gastrointest Liver Physiol 280: G879-G889, 2001;
0193-1857/01 $5.00
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Vol. 280, Issue 5, G879-G889, May 2001

In vivo recognition of mannosylated proteins by hepatic mannose receptors and mannan-binding protein

Praneet Opanasopit, Keiko Shirashi, Makiya Nishikawa, Fumiyoshi Yamashita, Yoshinobu Takakura, and Mitsuru Hashida

Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan

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 111In-mannosylated proteins were taken up mainly by liver, and uptake was saturated with increasing doses. 111In-Man-superoxide dismutases and 111In-Man12- and 111In-Man16-BSA had simple dose-dependent pharmacokinetic profiles, whereas other derivatives (111In-Man25-, -Man35-, and -Man46-BSA and 111In-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 111In-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.

mannose-specific lectin; pharmacokinetics; liver; drug delivery


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