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Lactosaminated human serum albumin as hepatotropic drug carrier
Author(s) -
Fiume L.,
Busi C.,
Mattioli A.
Publication year - 1982
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(82)80701-1
Subject(s) - humanities , human serum albumin , medicine , library science , philosophy , chemistry , computer science , biochemistry
In chronic hepatitis B infection, adenine-9-fl-Darabinofuranoside (ara-A) reduces, in a dose dependent fashion, the serum levels of virus DNApolymerase [1-4] with an improvement in liver function and histology [5] and a loss of infectivity in some patients [4]. However this drug produces dose-dependent side effects [6-8] which might be avoided or reduced by selectively delivering ara-A to hepatocytes. In mice, liver targeting of ara-A has been obtained by conjugation with asialofetuin (AF) [9] or with lactosaminated serum albumin (LSA) [10], two galactosyl-terminating glycoproteins which penetrate by a receptor-mediated endocytosis only in hepatocytes where they are digested in lysosomes [11-16]. AF-a ra -A and L-SA-ara-A conjugates, administered to mice with Ectromelia virus-hepatitis, inhibited virus DNA synthesis in liver without producing significant inhibition of cellular DNA synthesis in intestine and bone marrow [9,10]. L-SA has a definitive advantage over AF as hepatotropic carrier of ara-A since conjugates prepared with lactosaminated homologous albumin are not immunogenic, at least in mice, to the contrary of AF conjugates which are strong antibody inducers [17]. Moreover as opposed to naturally occurring glycoproteins of human blood, which after desialylation are also taken up by hepatocytes [12], L-(human)SA (L-HSA) can easily be obtained in the amounts required for clinical purposes. By receptor-mediated endocytosis proteins enter into cells only in limited amounts; the hepatic uptake of AF in rats does not exceed 0.18/~g. g body wt -1 • min l [18]. In the present experiments we have calculated the maximal rate of hepatic uptake in mice of two L-HSA preparations with 22 and 40 galactosyl residues, respectively. Moreover, we have determined the minimal doses of free or conjugated ara-A which inhibit DNA synthesis in liver of Ectromelia virus-infected mice. These experiments were undertaken in order to calculate whether the amounts of ara-A needed to exert antiviral activity in chronic hepatitis B can be transported to hepatocytes by L-HSA.