A novel injectable water-soluble amphotericin B-arabinogalactan conjugate

New, stable, highly water-soluble, nontoxic polysaccharide conjugates of am photericin B (AmB) are described. AmB was conjugated by a Schiff-base react ion with oxidized arabinogalactan (AG). AG is a highly branched natural pol ysaccharide with unusual water solubility (70% in water). A high yield of a ctive AmB was obtained with the conjugates which were similarly highly wate r soluble and which could be appropriately formulated for injection. They s howed comparable MICs for Candida albicans and Cryptococcus neoformans (MIC s, 0.1 to 0.2 mu g/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37 degrees C, was nonhemolytic and was much safer than c onventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjug ate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. Th is conjugate, similarly to the liposomal formulation (AmBisome), was more e ffective than AmB-deoxycholate in prolonging survival. It was more effectiv e than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after furt her development of the AmB-AG conjugate, it may be a potent agent in the tr eatment of fungal infections.