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Published on: October 13, 2010
Amphotericin B-phospholipid interactions responsible for reduced mammalian cell toxicity
W R Perkins1, S R Minchey, L T Boni
1Liposome Company, Inc., Princeton, NJ.
Biochimica Et Biophysica Acta
|June 30, 1992
Summary
Amphotericin B forms ribbon-like structures with phospholipids, reducing toxicity. These structures, observed via electron microscopy, show potential for stabilizing lipophilic drug delivery systems.
Area of Science:
- Biochemistry
- Materials Science
- Pharmacology
Background:
- Amphotericin B is a potent antifungal agent with significant toxicity.
- Lipid formulations aim to reduce Amphotericin B's adverse effects.
- Understanding drug-lipid interactions is crucial for developing safer drug delivery systems.
Purpose of the Study:
- To investigate the structural and functional properties of Amphotericin B-phospholipid interactions.
- To elucidate the mechanism behind the reduced toxicity of specific Amphotericin B-lipid complexes.
- To explore the potential of these structures in drug delivery applications.
Main Methods:
- Freeze-fracture and negative stain electron microscopy (EM) to visualize structures.
- Circular dichroism (CD) spectroscopy to analyze drug-lipid interactions.
- Assays to determine hemolytic activity and minimal inhibitory concentrations (MIC) against Candida albicans.
Main Results:
- Amphotericin B forms unique ribbon-like structures with phospholipids at specific molar ratios (1:3 to 1:1).
- These ribbon-like structures exhibit markedly reduced hemolytic activity compared to liposomal formulations.
- CD spectra revealed distinct interaction modes for liposomes versus ribbon-like structures.
- Drug-lipid complexation was observed above 3-4 mole percent Amphotericin B, leading to ribbon formation.
- Comparable MIC values for Candida albicans suggest effective antifungal activity despite structural changes.
- Lipase activity was identified as a factor in Amphotericin B release from ribbon-like structures.
- Headgroup interactions of phospholipids (DMPC, DMPG) played a minor role in ribbon formation.
Conclusions:
- Ribbon-like structures arise from phase separation of Amphotericin B-phospholipid complexes, curtailing drug release and toxicity.
- These findings suggest a novel role for lipids as stabilizing matrices for lipophilic drug delivery.
- Achieving highly ordered packing arrangements between lipids and drugs is key for developing safer and effective formulations.
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