title: Synthesis, characterisation and in vivo behaviour of a norfloxacin-poly(L-lysine citramide imide) conjugate bearing mannosyl residues.
abstract: With the aim of promoting the targeting of macrophage mannose receptors and the internalisation of the norfloxacin antibiotic, which is active against some intracellular bacteria, a macromolecular prodrug was synthesised where the antibiotic and mannosyl moieties were coupled to a polymeric carrier, namely poly(L-lysine citramide imide). This carrier, which derived from two metabolites, citric acid and L-lysine, is known to be biocompatible and slowly degradable under slight acidic conditions. Norfloxacin was coupled onto the acid groups present along the polymer chains, and conjugates were characterised by UV, TLC and SEC. The mannosyl groups selected to promote the targeting of the mannose-specific lectin present on the outer membrane of macrophages were incorporated through a biodegradable glycolic spacer arm. Two different strategies were considered to synthesise the full conjugates, namely coupling norfloxacin onto mannosylated conjugates, and coupling mannose onto PLCAI/Nflx conjugates. The second pathway led to better results regarding mannosylation. The presence of norfloxacin and mannose caused chain aggregation, especially for conjugates with a high content of mannosyl residues. The targeting ability of the prodrug was investigated using a method based on the competition between the mannosylated macromolecules and glucose oxidase, a mannosyl-bearing non-human protein. This method showed that prodrug macromolecules competed effectively with glucose oxidase and thus should be able to bring the drug up to the mannosyl receptor-bearing membranes of macrophages infected by intracellular bacteria.
authors.affiliation: CRBA-UPRESA CNRS 5473, Faculty of Pharmacy, Montpellier I University, France.
authors.forename: S
authors.initials: S
authors.lastname: Gac
authors.forename: J
authors.initials: J
authors.lastname: Coudane
authors.forename: M
authors.initials: M
authors.lastname: Boustta
authors.forename: M
authors.initials: M
authors.lastname: Domurado
authors.forename: M
authors.initials: M
authors.lastname: Vert
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D004337:Drug Carriers; D005949:Glucose Oxidase / Q000378:metabolism; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D051379:Mice; D009643:Norfloxacin / Q000008:administration & dosage*; D009757:Nylons; D011355:Prodrugs / Q000138:chemical synthesis*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D004337:Drug Carriers; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009757:Nylons; D011355:Prodrugs; D011956:Receptors, Cell Surface; C112977:poly(lysine citramide imide); D005949:Glucose Oxidase; D009643:Norfloxacin