title: Preparation of anti-HIV-low-density lipoprotein complexes for delivery of anti-HIV drugs via the low-density lipoprotein pathways.
abstract: Lipophilic prodrugs of 3'-azido-3'-deoxythymidine (AZT) and of 2',3'-didehydro-3'-deoxythymidine (D4T) have been synthesized. 3 beta-(2'-carboxymethoxy)-cholest-5-ene acid, palmitic acid, linolenic acid, linoleic acid, and cholanic acid have been covalently bound to AZT and D4T. In some experiments the fluorescent molecule NBD was simultaneously linked. These prodrugs were incorporated into LDL or acetylated LDL. The best incorporation was obtained with drugs presenting a steroid moiety (cholesterol derivative or cholanic acid) in their structure. The incorporation of prodrugs into LDL was estimated as approximately 200 molecules of prodrug per LDL particle. Cytofluorimetric studies clearly show that the NBD-steroid LDL or NBD-steroid acetylated LDL are bound and then internalized by the B-E receptor (U937) or the scavenger receptor (mouse peritoneal macrophage), respectively. The antiretroviral activity of palmitate-D4T, cholanic-AZT, and cholanic-AZT-LDL complex was similar to the activity of free D4T and free AZT, respectively. Development of lipid nucleoside-LDL complexes to attach specifically to cells involved in HIV infection might have a direct clinical relevance.
authors.affiliation: Pasteur Institute, INSERM U325, Lille, France.
authors.forename: H
authors.initials: H
authors.lastname: Sqalli-Houssaini
authors.forename: C
authors.initials: C
authors.lastname: Pierlot
authors.forename: J P
authors.initials: JP
authors.lastname: Kusnierz
authors.forename: B
authors.initials: B
authors.lastname: Parmentier
authors.forename: F
authors.initials: F
authors.lastname: Martin-Nizard
authors.forename: S
authors.initials: S
authors.lastname: Lestavel-Delattre
authors.forename: A
authors.initials: A
authors.lastname: Tartar
authors.forename: J C
authors.initials: JC
authors.lastname: Fruchart
authors.forename: C
authors.initials: C
authors.lastname: Sergheraert
authors.forename: P
authors.initials: P
authors.lastname: Duriez
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001667:Binding, Competitive; D002793:Cholic Acids / Q000737:chemistry; D004337:Drug Carriers; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D018119:Stavudine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D002793:Cholic Acids; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011355:Prodrugs; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C032531:apolipoprotein B,E receptor; D015215:Zidovudine; D018119:Stavudine; C007036:cholanic acid