title: Antileishmanial drug targeting through glycosylated polymers specifically internalized by macrophage membrane lectins.
abstract: Antileishmanial chemotherapy is hampered by the location of the parasite within the phagolysosome of the macrophage, which restricts the bioavailability of many potentially useful antileishmanial drugs. In this study, the possibility of using antileishmanial drugs targeted to the infected macrophages by means of a chemical linkage to a neutral mannose-substituted poly-L-lysine carrier molecule was explored. The study was performed in an in vitro model with Leishmania donovani-infected murine macrophages. The antileishmanial activities of various synthetic constructs were compared with those of the free drugs and the pentavalent antimonial Pentostam, which was used as the positive control. The 50% effective dose of allopurinol riboside linked to the mannosylated poly-L-lysine was below 7.5 x 10(-6) M, while it was up to 3 x 10(-4) M for the free drug, indicating that the drug bound to the polymer was 50 times more active than the free drug. Control experiments with other constructs (e.g., allopurinol riboside linked to the mannose-free polymer) confirmed that the enhancement of activity was indeed achieved by means of the mannose homing device.
authors.affiliation: Département de Biochimie des Glycoconjugués et des Lectines Endogènes, Orléans, France.
authors.forename: E
authors.initials: E
authors.lastname: Nègre
authors.forename: M L
authors.initials: ML
authors.lastname: Chance
authors.forename: S Y
authors.initials: SY
authors.lastname: Hanboula
authors.forename: M
authors.initials: M
authors.lastname: Monsigny
authors.forename: A C
authors.initials: AC
authors.lastname: Roche
authors.forename: R M
authors.initials: RM
authors.lastname: Mayer
authors.forename: M
authors.initials: M
authors.lastname: Hommel
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D002462:Cell Membrane / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis; D006031:Glycosylation; D007893:Leishmania donovani / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D011108:Polymers / Q000138:chemical synthesis; D051381:Rats
chemical_list: D000981:Antiprotozoal Agents; D004337:Drug Carriers; D011108:Polymers; D000967:Antimony Sodium Gluconate