Abstract
Hepatitis B virus (HBV) infection is the world's most important chronic virus infection. No safe and effective treatment is available at present, and clinical exploration of promising antiviral agents, such as nucleoside analogues is hampered because of significant side-effects due to their aspecific body distribution. We are exploring the possibility of the selective delivery of antiviral active drugs to liver parenchymal cells, the main site of infection and replication of HBV. Chylomicrons, which transport dietary lipids into the liver via apolipoprotein E-specific receptors, could serve as drug carriers. However, their endogenous nature hampers their application as pharmaceutical drug carriers. We report here that incorporation of a derivative of the nucleoside analogue iododeoxy-uridine into recombinant chylomicrons leads to selective targeting to liver parenchymal cells. Potentially effective intracellular drug concentrations of 700 nM can be achieved, and we therefore anticipate that these drug carrier complexes represent a conceptual advance in the development of an effective and safe therapy for hepatitis B.
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References
Tiollais, P., Pourcel, C. & Dejean, A. The hepatitis B virus. Nature (London) 317, 489–495 (1985).
Yoffe, B. & Noonan, C.A. Hepatitis B virus: new and evolving issues. Digest. Dis. Sci. 37, 1–9 (1992).
Beasley, R.P., Hwang, L.Y., Lin, C.C. & Chien, C.S. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22 707 men in Taiwan. Lancet 2, 1129–1133 (1981).
Beasley, R.P. The major etiology of hepatocellular carcinoma. Cancer 61, 1942–1956 (1988).
Ueda, K., Tsurimoto, T., Nagahata, T., Chisaka, O. & Matsubara, K., An in vitro system for screening anti-hepatitis B virus drugs. Virology 169, 213–216 (1989).
Weller, I.V.D. et al. Acyclovir inhibits hepatitis B virus replication in man. J. antimicrob. Chemother. 11, 223–231 (1983).
Hoofnagle, J.H. et al. Randomized control trial of adenine arabinoside monophosphate for chronic type B hepatitis. Gastroenterology 86, 150–157 (1984).
Lok, A.S.F., Wilson, L.A. & Thomas, H.C. Neurotoxicity associated with adenine arabinoside monophosphate in the treatment of chronic hepatitis B virus infection. J. antimicrob. Chemother. 14, 93–99 (1984).
Summers, J. & Mason, W.S. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29, 403–115 (1982).
Seeger, C., Ganem, D. & Varmus, H.E. Biochemical and genetic evidence for the hepatitis B replication strategy. Science 232, 477–484 (1986).
Mahley, R.W. & Hussain, M.M. Chylomicron and chylomicron remnant catabolism. Carr. Opin. Lipidol. 2, 170–176 (1991).
Hoeg, J.M., Demosky, S.J. Jr, Gregg, R.E., Schaefer, E.J. & Brewer, H.B. Jr Distinct hepatic receptors for low density lipoprotein and apolipoprotein E in humans. Science 227, 759–761 (1985).
Bijsterbosch, M.K. & van Berkel, Th.J.C. Native and modified lipoproteins as drug delivery systems. Adv. Drug Delivery Rev. 5, 231–251 (1990).
Shaw, J.M. ed Lipoproteins as carriers of pharmaceutical agents (Marcel Dekker, Inc, New York, 1991).
Van Dijk, M.C.M. et al. Recognition of chylomicron remnants and β-migrating very-low-density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver α2-macroglobulin-recognition site. Biochem. J. 279, 863–870 (1991).
Mahley, R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622–630 (1988).
Windier, E., Chao, Y.S. & Havel, R.J. Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat: opposing effects of homologous apolipoprotein E and individual C apoproteins. J. Boil. Chem. 255, 8303–8307 (1980).
Van Berkel, Th.J.C., Kruijt, J.K., Scheek, L.M. & Groot, P.H.E. Effect of apolipoproteins E and C-III on the interaction of chylomicrons with parenchymal and non-parenchymal cells from rat liver. Biochem. J. 216, 71–80 (1983).
Vogel, T. et al. Human apolipoprotein E expression in Escherichia coli: structural and functional identity of the bacterially produced protein with plasma apolipoprotein E. Proc. natn. Acad. Sci. U.S.A. 82, 8696–8700 (1985).
Huettinger, M., Retzek, H., Eder, M. & Goldenberg, H. Characteristics of chylomicron remnant uptake into rat liver. Clin. Biochem. 21, 87–92 (1988).
Chen, Z., Keech, A. et al. Prolonged infection with hepatitis B virus and association between low blood cholesterol concentration and liver cancer. Brit. med. J. 306, 890–894 (1993).
Price, P.M., Banerjee, R. & Acs, G. Inhibition of the replication of hepatitis B virus by the carbocyclic analog of 2′-deoxyguanosine. Proc. natn. Acad. Sci. U.S.A. 86, 8543–8544 (1989).
Lin, T.S. et al. Synthesis and biological evaluation of 2′,3′-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). J. med. Chem. 37, 798–803 (1994).
Summers, J., Smolec, J.M. & Snyder, R. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc. natn. Acad. Sci. U.S.A. 75, 4533–4537 (1978).
Tennant, B.D. & Gerin, J.L. The woodchuck model of hepatitis B virus infection. In: The Liver: Biology and Pathobiology (eds. Arias, I.M. et al.) 1455–1466 (Raven, New York 1994).
Périgaud, C., Gosselin, G. & Imbach, J.L. Nucleoside analogues as chemotherapeutic agents; a review. Nucleos. Nucleot. 11, 903–945 (1992).
Sacks, S.L. et al. Toxicity of vidarabine. JAMA 241, 28–29 (1979).
Sacks, S.L. et al. Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination. Antimicrob. Agents Chemother. 21, 93–100 (1982).
Redgrave, T.G. & Maranhao, R.C. Metabolism of protein-free lipid emulsion models of chylomicrons in rats. Biochim. biophys. Acta. 835, 104–112 (1985).
Bijsterbosch, M.K., Schouten, D. & van Berkel, Th.J.C. Synthesis of the dioleoyl derivative of iododeoxyuridine and its incorporation into reconstituted high density lipoprotein particles. Biochemistry 33, 14073–14080 (1994).
Bijsterbosch, M.K., Ziere, G.J. & van Berkel, Th.J.C. Lactosylated low density lipoprotein: a potential carrier for the site-specific delivery of drugs to Kupffer cells. Mol. Pharmacol. 36, 484–489 (1989).
Van Berkel, Th.J.C., Dekker, C.J., Kruijt, J.K. & van Eijk, H.G. The interaction in vivo of transferrin and asialotransferrin with liver cells. Biochem. J. 243, 715–722 (1987).
Blouin, A., Bolender, R.D. & Weibel, E.R. Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma: a stereological study. J. Cell. Biol. 72, 441–455 (1977).
Nagelkerke, J.F., Barto, K.P. & van Berkel, Th.J.C. In vivo and in vitro uptake and degradation of acetylated low density lipoprotein by rat liver endothelial, Kupffer and parenchymal cells. J. biol. Chem. 258, 12221–12227 (1983).
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Rensen, P., Van Dijk, M., Havenaar, E. et al. Selective liver targeting of antivirals by recombinant chylomicrons — a new therapeutic approach to hepatitis B. Nat Med 1, 221–225 (1995). https://doi.org/10.1038/nm0395-221
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DOI: https://doi.org/10.1038/nm0395-221
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