title: Acetylated low-density lipoprotein as a vehicle for antiinfectious drugs: preparation and antileishmanial activity of Ac-LDL containing ketoconazole-oleate.
abstract: Previous studies have demonstrated that mouse peritoneal macrophages take up low-density lipoproteins (LDL) which have been chemically modified by the acetylation of lysine residues (Ac-LDL). This uptake is mediated through a specific receptor known as the scavenger receptor. Ac-LDL therefore appear to have excellent potential for antiinfectious drug targeting. We have developed a new method to incorporate ketoconazole-oleate, a lipophilic derivative of ketoconazole, into Ac-LDL. The method involves solubilization of LDL in the presence of Na deoxycholate, the addition of a micellar solution of the drug to be incorporated, and the subsequent removal of the detergent leading to the formation of reconstituted LDL (referred to as LDL-KOL). The LDL-KOL contain 200 drug molecules per LDL particle and compete for the binding of native 125I-LDL on human skin fibroblast monolayers. Furthermore, reconstituted LDL-KOL are indistinguishable from native LDL with regard to lipid composition and electrophoretic mobility. LDL-KOL, when acetylated, are recognized by the scavenger receptor. Acetylated LDL-KOL show antileishmanial activity when tested on infected macrophages. The activity appears to be mediated through the scavenger-cell pathway, as LDL-KOL are inactive under the same conditions. Moreover, acetylated LDL-KOL are selectively accumulated within infected macrophages rather than in normal cells. This may be of value in the treatment of intracellular infections.
authors: Medgenix Group, C/O Ire B3, Fleurus, Belgium.
authors: J M
authors: JM
authors: Nicolas
authors: P
authors: P
authors: Pirson
authors: B
authors: B
authors: Leclef
authors: A
authors: A
authors: Trouet
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D007654:Ketoconazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007896:Leishmaniasis / Q000188:drug therapy*; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D009829:Oleic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D014677:Pharmaceutical Vehicles
chemical_list: D000981:Antiprotozoal Agents; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D014677:Pharmaceutical Vehicles; C032629:acetyl-LDL; C066633:ketoconazole oleate; D007654:Ketoconazole