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Characterization of a Polyethylene Glycol-Amphotericin B Conjugate Loaded with Free AMB for Improved Antifungal Efficacy

Team Photo of PLoS One 2016 11(3): e0152112
From Left: Hoi Kong Meng, Tessa Tan and Dr Ng Say Kong

Authors

Tessa Rui Min Tan1, Kong Meng Hoi1, Peiqing Zhang1,2, Say Kong Ng1,3

1 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
2 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore

Published in PLoS One 2016 11(3): e0152112 (Online Version)

 

Abstract

Amphotericin B (AMB) is an antifungal drug used intravenously to treat serious systemic fungal infections. Clinical usage of conventional AMB is limited by the drug’s severe side effects, including hypotension, kidney damage and multiple organ damage. This can be partially due to AMB’s toxicity to mammalian cells because the fungal targets are similar to those found in mammalian cell membranes. AMB is also highly hydrophobic and has low solubility, which may limit its formulation and dosage.

The functionalized polyethylene glycol (PEG) chemical group is highly soluble, has low toxicity and is commonly used in pharmaceutical products. By reacting AMP with PEG, we obtained a formulation. Analyzing this new product using chromatographic separation methods, we demonstrated that this AMB-PEG formulation contains both chemically conjugated AMB-PEG and free AMB that is physically associated with the conjugate, and that reacting AMB and PEG in a 2:1 ratio resulted in more free AMB loaded into the chemical complex. The AMB-PEG formulation with more AMB showed improved antifungal efficacy in vitro, with similar low in vitro toxicity to mammalian cells. In comparison to conventional AMB, the AMB-PEG formulation with more free AMB is two times less toxic to mammalian cells in vitro at conventional doses against Candida albicans and Cryptococcus neoformans. This study thus demonstrates that AMB-PEG can be a viable alternative formulation of this effective antifungal drug.

Figure 1. Images of HEK293 and IMR-90 human cell lines after 24 hours exposure to AMB-PEG obtained from 1 AMB : 1 PEG or 2 AMB : 1 PEG reaction, and unconjugated AMB, at different concentrations. Live cells are stained green and dead cells stained red.