In this study, we tested the efficacy of
amphotericin B (AmB)-
arabinogalactan (AmB-AG) conjugates for the treatment of experimental
leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible
polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the
drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED(50)s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 microg/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 microg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED(50)s of 0.035 microg/ml for rAmB-AG and 0.027 microg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of
body weight) and
Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than
Fungizone.
Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established
infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial
infections. The conjugates, which are stable and can be produced relatively cheaply (compared to
lipid formulations), can be used in the future for the treatment of
leishmaniasis infections.