Drug targeting to the liver with lactosylated albumins: Does the glycoprotein target the drug or is the drug targeting the glycoprotein?
Corresponding Author
Peter van der Sluijs M.D.
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Department of Pharmacology and Therapeutics, Drug Design and Development Program, University of Groningen, Ant. Deusinglaan 2, NL-9713 AW Groningen, The Netherlands===Search for more papers by this authorHans P. Bootsma
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorBart Postema
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorFrits Moolenaar
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorDirk K. F. Meijer
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorCorresponding Author
Peter van der Sluijs M.D.
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Department of Pharmacology and Therapeutics, Drug Design and Development Program, University of Groningen, Ant. Deusinglaan 2, NL-9713 AW Groningen, The Netherlands===Search for more papers by this authorHans P. Bootsma
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorBart Postema
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorFrits Moolenaar
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorDirk K. F. Meijer
Department of Pharmacology and Therapeutics, University of Groningen, Groningen, The Netherlands
Search for more papers by this authorAbstract
The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drugcarrier conjugate fluorescein-lactosylated albumin (F-LnHSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytosed neoglycoprotein. Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactoseterminated glycoproteins. Clearance experiments with fluoresceinated 125I-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (∼90%) inhibition of hepatic uptake, while also a pronounced effect was obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein permole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neoglycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of “inversed targeting” could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.
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