title: Utility of poly(ethylene glycol) conjugation to create prodrugs of amphotericin B.
abstract: This paper reports on the synthesis, safety, and efficacy of a series of water-soluble derivatives of poly(ethylene glycol) (PEG)-conjugated amphotericin B (AmB). PEG 40 000 attached to the sugar amino group of AmB via labile carbamate and carbonate linkages was examined. The synthetic program conducted for this investigation provided a series of disubstituted PEG-AmB derivatives which had in vitro PEG half-life of hydrolyses rates in rat plasma varying between 1 and 3 h. Importantly, all conjugates demonstrated less than 6% hydrolysis following 24 h incubation in pH 7.4 phosphate buffer at 25 degrees C and showed solubilities greater than 46 mg/mL in aqueous solutions. The solubility of AmB in the conjugates increased up to approximately 200 times compared to unmodified AmB in saline. As a major finding, this investigation demonstrated that conjugation of PEG to AmB could produce conjugates that were significantly (6x) less toxic than AmB-deoxycholate and maintained, or even had enhanced, in vivo antifungal activity.
authors.affiliation: Enzon Pharmaceutical, Inc., 20 Kingsbridge Road, Piscataway, New Jersey 08854-3998, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Conover
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Clifford B
authors.initials: CB
authors.lastname: Longley
authors.forename: Kwok L
authors.initials: KL
authors.lastname: Shum
authors.forename: Richard B
authors.initials: RB
authors.lastname: Greenwald
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011355:Prodrugs; D011092:Polyethylene Glycols; D000666:Amphotericin B