文章基本信息
- 标题：Reconstituted high density lipoprotein enriched with the polyene antibiotic amphotericin B
- 本地全文：下载
- 作者：Oda, Michael N. ; Hargreaves, Peter L. ; Beckstead, Jennifer A. 等
- 期刊名称：JLR Papers In Press
- 印刷版ISSN：0022-2275
- 电子版ISSN：1539-7262
- 出版年度：2006
- 卷号：47
- 期号：2
- 页码：260-267
- DOI：10.1194/jlr.D500033-JLR200
- 出版社：American Society for Biochemistry and Molecular Biology
- 摘要：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
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