Utility of poly(ethylene glycol) conjugation to create prodrugs of amphotericin B.
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.
Conover
Charles D
CD
Enzon Pharmaceutical, Inc., 20 Kingsbridge Road, Piscataway, New Jersey 08854-3998, USA.
Zhao
Hong
H
Longley
Clifford B
CB
Shum
Kwok L
KL
Greenwald
Richard B
RB
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
D011355:Prodrugs; D011092:Polyethylene Glycols; D000666:Amphotericin B