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Antimicrobial Agents and Chemotherapy, August 1999, p. 1975-1981, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Novel Injectable Water-Soluble Amphotericin B-Arabinogalactan Conjugate

Rama Falk,1 Abraham J. Domb,2 and Itzhack Polacheck1,*

Department of Clinical Microbiology and Infectious Diseases, The Hebrew University-Hadassah Medical Center,1 and Department of Medicinal Chemistry, The Hebrew University of Jerusalem-School of Pharmacy,2 Jerusalem, Israel

Received 3 December 1998/Returned for modification 27 January 1999/Accepted 28 May 1999

New, stable, highly water-soluble, nontoxic polysaccharide conjugates of amphotericin B (AmB) are described. AmB was conjugated by a Schiff-base reaction with oxidized arabinogalactan (AG). AG is a highly branched natural polysaccharide with unusual water solubility (70% in water). A high yield of active AmB was obtained with the conjugates which were similarly highly water soluble and which could be appropriately formulated for injection. They showed comparable MICs for Candida albicans and Cryptococcus neoformans (MICs, 0.1 to 0.2 µg/ml). The reduced AmB conjugate, which was synthesized at pH 11 for 48 h at 37°C, was nonhemolytic and was much safer than conventional micellar AmB-deoxycholate. It was the least toxic AmB-AG conjugate among those tested with mice (maximal tolerated dose, 50 mg/kg of body weight), and histopathology indicated no damage to the liver or kidneys. This conjugate, similarly to the liposomal formulation (AmBisome), was more effective than AmB-deoxycholate in prolonging survival. It was more effective than both the liposomal and the deoxycholate formulations in eradicating yeast cells from target organs. The overall results suggest that after further development of the AmB-AG conjugate, it may be a potent agent in the treatment of fungal infections.

* Corresponding author. Mailing address: Department of Clinical Microbiology and Infectious Diseases, The Hebrew University-Hadassah Medical Center, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-677-6592. Fax: 972-2-676-9206. E-mail: polacek{at}md2.huji.ac.il.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1975-1981, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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