Sarah Kagan

Publications (3)8.98 Total impact

• Article: Mechanism of activity and toxicity of Nystatin-Intralipid.

  Rita Semis, Sarah Kagan, Israela Berdicevsky, Itzhack Polacheck, Esther Segal
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  ABSTRACT: A novel lipid formulation of Nystatin (NYT), Nystatin-Intralipid (NYT-IL), which was found to be more active and less toxic in vitro and in vivo, was developed in our laboratory. The aim of the present study was to explore the possible mechanisms underlying its biological activity. To assess mechanisms affecting fungal cells we conducted the following experiments: killing kinetics, scanning and transmission electron microscopy (EM), measurements of potassium ion leakage and susceptibility in the presence of ergosterol. To study mechanisms affecting mammalian cells, we evaluated the effect of NYT-IL on a kidney cell line, with respect to viability, metabolic activity, potassium leakage and internalization of FITC-labeled human transferrin. NYT-IL exhibited killing kinetics patterns against Candida albicans similar to those of NYT and caused disruption of fungal cells and potassium ion leakage. Susceptibility tests showed that NYT-IL had lower antifungal activity in the presence of ergosterol. Thus, NYT-IL acts apparently by damaging fungal membrane, possibly through interaction with ergosterol, and maybe by additional modes of action. NYT-IL did not cause potassium leakage from mammalian kidney cells at any tested concentration and was not cytotoxic, whereas NYT, at high concentrations, led to K(+) leakage and was cytotoxic. Furthermore, the high NYT concentration interfered in the internalization process of human transferrin receptor (hTfnR) while NYT-IL did not. In summary, the Intralipid formulation of NYT diminishes the mechanisms responsible for toxicity to mammalian cells but preserves mechanisms of action against fungi, thereby suggesting superiority of NYT-IL as compared to NYT as an antifungal agent.
  Medical mycology: official publication of the International Society for Human and Animal Mycology 10/2012; · 2.13 Impact Factor
• Article: Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan.

  Sarah Kagan, Diana Ickowicz, Miriam Shmuel, Yoram Altschuler, Edward Sionov, Miriam Pitusi, Aryeh Weiss, Shimon Farber, Abraham J Domb, Itzhack Polacheck
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  ABSTRACT: Amphotericin B (AMB) is an effective antifungal agent. However, its therapeutic use is hampered by its toxicity, mainly due to channel formation across kidney cell membranes and the disruption of postendocytic trafficking. We previously described a safe injectable AMB-arabinogalactan (AG) conjugate with neutralized toxicity. Here we studied the mechanism of the toxicity of free AMB and its neutralization by conjugation with AG. AMB treatment of a kidney cell line modulated the trafficking of three receptors (C-X-C chemokine receptor type 4 [CXCR4], M1 receptor, and human transferrin receptor [hTfnR]) due to an increase in endosomal pH. Similar data were also obtained in yeast but with an increase in vacuolar pH and the perturbation of Hxt2-green fluorescent protein (GFP) trafficking. The conjugation of AMB with AG neutralized all elements of the toxic activity of AMB in mammalian but not in fungal cells. Based on these results, we provide an explanation of how the conjugation of AMB with AG neutralizes its toxicity in mammalian cells and add to the knowledge of the mechanism of action of free AMB in both fungal and mammalian cells.
  Antimicrobial Agents and Chemotherapy 08/2012; 56(11):5603-11. · 4.84 Impact Factor
• Article: Galactomannan–amphotericin B conjugate: synthesis and biological activity

  Shimon Farber, Diana Ickowicz, Edward Sionov, Sarah Kagan, Itzhack Polacheck, Abraham J. Domb
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  ABSTRACT: Polysaccharide conjugated amphotericin B (AmB) was synthesized by conjugation of AmB to oxidized galactomannan (GM) by reductive amination and tested for antifungal activity. AmB conjugates were investigated for their ability to inhibit Candida albicans growth. Antifungal efficiency of the synthetic AmB–GM depends on both, AmB content and duration of exposure. The most potent compound was a conjugate which contains 40% AmB with minimal inhibition concentration of 0.25 mg/l. In vitro toxicity analysis revealed that conjugates with 20, 30, and 40% w/w AmB content have no hemolytic effect and no influence on the viability of the VERO kidney cells. Furthermore, maximal tolerant dose (MTD) of the conjugate was determined in vivo and found to be 60 mg/kg (equivalent to AmB), while commercial Fungizone® demonstrated increased toxicity of 3 mg/kg on mice model. Copyright © 2010 John Wiley & Sons, Ltd.
  Polymers for Advanced Technologies 12/2010; 22(1):119 - 125. · 2.01 Impact Factor