Activity, reduced toxicity, and scale-up synthesis of amphotericin B-conjugated polysaccharide

Diana E. Ickowicz, Shimon Farber, Edward Sionov, Sarah Kagan, Amnon Hoffman, Itzhack Polacheck, Abraham J. Domb*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Amphotericin B (AMB) arabinogalactan (AG) conjugate was synthesized by the conjugation of AMB to oxidized AG by reductive amination. The conjugate was evaluated for in vitro antifungal activity and in vivo toxicity. Optimization of the conjugation process was investigated using large batches of 100 g, which are 20 times larger than previously reported for AMB-AG conjugation. The efficacy of AMB-AG conjugates was studied as a function of reaction conditions and time, aldehyde/reducing agent mole ratio, and purification procedure. The most potent AMB-AG conjugate having low minimal inhibitory concentration (MIC) and high maximal tolerated dose (MTD) was obtained following reduction with NaBH4 at 1:2 mol ratio (AG units/NaBH4) at 25 °C for 24 h. AMB-AG conjugate prepared under these conditions demonstrated MIC of 0.5 mg/L (equiv of AMB) in Candida albicans, and an MTD of 60 mg/kg (equiv of AMB) in mice, while AMB clinical formulation (Fungizone) demonstrated high toxicity (MTD = 3 mg/kg). These findings confirm the simplicity and reproducibility of the conjugation allowing this method to be applied on larger scale production.

Original languageAmerican English
Pages (from-to)2079-2089
Number of pages11
JournalBiomacromolecules
Volume15
Issue number6
DOIs
StatePublished - 9 Jun 2014

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