title: Selective liver targeting of antivirals by recombinant chylomicrons--a new therapeutic approach to hepatitis B.
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 iododeoxyuridine 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.
authors.affiliation: Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, The Netherlands.
authors.forename: P C
authors.initials: PC
authors.lastname: Rensen
authors.forename: M C
authors.initials: MC
authors.lastname: van Dijk
authors.forename: E C
authors.initials: EC
authors.lastname: Havenaar
authors.forename: M K
authors.initials: MK
authors.lastname: Bijsterbosch
authors.forename: J K
authors.initials: JK
authors.lastname: Kruijt
authors.forename: T J
authors.initials: TJ
authors.lastname: van Berkel
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000737:chemistry; D001692:Biological Transport; D002914:Chylomicrons / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006509:Hepatitis B / Q000188:drug therapy*; D007065:Idoxuridine / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018110:Receptors, Lipoprotein / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D001057:Apolipoproteins E; D002914:Chylomicrons; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D007065:Idoxuridine