HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) An erratum has been published All Versions of this Article: D500033-JLR200v1 47/2/260    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Oda, M. N. Articles by Ryan, R. O. Search for Related Content PubMed PubMed Citation Articles by Oda, M. N. Articles by Ryan, R. O. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 47, 260-267, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Reconstituted high density lipoprotein enriched with the polyene antibiotic amphotericin B

Michael N. Oda^*, Peter L. Hargreaves^*, Jennifer A. Beckstead^*, Katherine A. Redmond^*, Rik van Antwerpen and Robert O. Ryan^1,*

^* Lipid Biology in Health and Disease Research Group, Children's Hospital Oakland Research Institute, Oakland, CA 94609
Department of Biochemistry, Virginia Commonwealth University, Richmond, VA 23298

Published, JLR Papers in Press, November 28, 2005.

¹ To whom correspondence should be addressed. e-mail: rryan{at}chori.org

The polyene antibiotic amphotericin B (AMB) is an effective antifungal agent whose therapeutic potential is limited by poor aqueous solubility and toxicity toward host tissues. Addition of apolipoprotein A-I to a multilamellar phospholipid vesicle dispersion containing 20% (w/w) AMB induces the formation of reconstituted high density lipoprotein (rHDL), with solubilization of the antibiotic. Density gradient ultracentrifugation resulted in flotation of the complexes to a density of 1.16 g/ml, and negative stain electron microscopy revealed a population of disk-shaped particles. Native gradient polyacrylamide gel electrophoresis indicated a particle diameter of 8.5 nm. Absorbance spectroscopy provided evidence for AMB integration into the lipid milieu. AMB-rHDLs were potent inhibitors of Saccharomyces cerevisiae growth, yielding 90% growth inhibition at <1 µg/ml yeast culture. In studies with pathogenic fungal species, similar growth inhibition characteristics were observed. Compared with AMB-deoxycholate micelles, AMB-rHDL displayed greatly attenuated red blood cell hemolytic activity and decreased toxicity toward cultured hepatoma cells. In in vivo studies in immunocompetent mice, AMB-rHDLs were nontoxic at 10 mg/kg, and they showed efficacy in a mouse model of candidiasis at concentrations as low as 0.25 mg/kg. These results indicate that AMB-rHDLs constitute a novel formulation that effectively solubilizes the antibiotic and elicits strong in vitro and in vivo antifungal activity with no observed toxicity at therapeutic doses.

Supplementary key words apolipoprotein • phospholipid • Saccharomyces cerevisiae • fungus • Candida albicans • red blood cell • drug delivery • density gradient ultracentrifugation • electron microscopy

Abbreviations: AMB, amphotericin B; apoA-I, apolipoprotein A-I; DMPC, dimyristoylphosphatidylcholine; DMPG, dimyristoylphosphatidylglycerol; IC₉₀, concentration at which 90% growth inhibition occurs; RBC, red blood cell; rHDL, reconstituted high density lipoprotein; YEPD, yeast extract peptone glucose broth medium

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. G. Nelson, J. V. Bishop, R. O. Ryan, and R. Titus Nanodisk-Associated Amphotericin B Clears Leishmania major Cutaneous Infection in Susceptible BALB/c Mice Antimicrob. Agents Chemother., April 1, 2006; 50(4): 1238 - 1244. [Abstract] [Full Text] [PDF]