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Activity, reduced toxicity, and scale-up synthesis of amphotericin B-conjugated polysaccharide
Year:
2014
Source of publication :
Biomacromolecules
Authors :
Sionov, Edward
;
.
Volume :
15
Co-Authors:
Ickowicz, D.E., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Farber, S., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Sionov, E., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Kagan, S., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Hoffman, A., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Polacheck, I., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Domb, A.J., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel, Israel and Jerusalem College of Engineering (JCE), Jerusalem 9103501, Israel
Facilitators :
From page:
2079
To page:
2089
(
Total pages:
11
)
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. © 2014 American Chemical Society.
Note:
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More details
DOI :
10.1021/bm5002125
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
28560
Last updated date:
02/03/2022 17:27
Creation date:
17/04/2018 00:40
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Scientific Publication
Activity, reduced toxicity, and scale-up synthesis of amphotericin B-conjugated polysaccharide
15
Ickowicz, D.E., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Farber, S., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Sionov, E., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Kagan, S., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Hoffman, A., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel
Polacheck, I., Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
Domb, A.J., Institute of Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel, Israel and Jerusalem College of Engineering (JCE), Jerusalem 9103501, Israel
Activity, reduced toxicity, and scale-up synthesis of amphotericin B-conjugated polysaccharide
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. © 2014 American Chemical Society.
Scientific Publication
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