Synthesis, characterisation and in vivo behaviour of a norfloxacin-poly(L-lysine citramide imide) conjugate bearing mannosyl residues

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 wher e the antibiotic and mannosyl moieties were coupled to a polymeric carrier, namely poly(l-lysine citramide imide). This carrier, which derived from tw o metabolites, citric acid and L-lysine, is known to be biocompatible and s lowly degradable under slight acidic conditions. Norfloxacin was coupled on to the acid groups present along the polymer chains, and conjugates were ch aracterised 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 man nose onto PLCAI/Nflx conjugates. The second pathway led to better results r egarding mannosylation, The presence of norfloxacin and mannose caused chai n aggregation, especially for conjugates with a high content of mannosyl re sidues. The targeting ability of the prodrug was investigated using a metho d based on the competition between the mannosylated macromolecules and gluc ose oxidase, a mannosyl-bearing non-human protein. This method showed that prodrug macromolecules competed effectively with glucose oxidase and thus s hould be able to bring the drug up to the mannosyl receptor-bearing membran es of macrophages infected by intracellular bacteria.