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Effects of the aggregation state of amphotericin B on its toxicity to mice
J Barwicz1, S Christian, I Gruda
1Département de Chimie-Biologie, Université du Québec, Trois-Rivières, Canada.
Abstract:
Amphotericin B (AmB) is a very effective antifungal agent for most systemic fungal infections. However, the relatively high toxicity of this drug imposes limits on its clinical usefulness. Most of the current work in this field is devoted to the search for less-toxic formulations of the drug. Here we describe the effects of three surfactants, one anionic and the other two nonionic, on the aggregation state of AmB in solutions which were injected intravenously into mice. The degree of aggregation of AmB was monitored spectroscopically and by light scattering. The toxicity was expressed as percentage of survivors. These results were compared with those obtained with doses of AmB the same as those present in a commercial formulation of AmB, Fungizone. Two surfactants, lauryl sucrose and sodium deoxycholate, used at concentrations which induced monomerization of AmB, substantially decreased the acute toxicity of AmB to mice. Conversely, the third surfactant, Tween 80, showed a synergistic potentiation of the toxicity of the antibiotic. A good correlation was found between the in vivo toxicity and the aggregation state of AmB in injected solutions. Solutions in which AmB was almost entirely monomeric were half as toxic after 24 h and about six times less toxic after 1 week than the corresponding solutions of Fungizone.
Insights
Surfactants can reduce Amphotericin B (AmB) toxicity by altering its aggregation state. Monomeric AmB formulations showed significantly lower acute toxicity in mice compared to standard formulations.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Amphotericin B (AmB) is a potent antifungal drug but exhibits significant toxicity, limiting its clinical use.
- Developing less toxic AmB formulations is crucial for managing systemic fungal infections.
- The aggregation state of AmB influences its efficacy and toxicity profile.
Purpose of the Study:
- To investigate the impact of anionic and nonionic surfactants on Amphotericin B (AmB) aggregation.
- To evaluate the effect of surfactant-induced AmB monomerization on its in vivo toxicity in mice.
- To compare the toxicity of modified AmB formulations with a commercial preparation (Fungizone).
Main Methods:
- Spectroscopic analysis and light scattering were used to monitor AmB aggregation state in solution.
- Intravenous injection of AmB-surfactant solutions into mice to assess acute toxicity.
- Survival rates of mice were recorded to quantify toxicity at different time points (24 hours and 1 week).
Main Results:
- Two surfactants, lauryl sucrose and sodium deoxycholate, induced AmB monomerization and substantially decreased its acute toxicity in mice.
- Conversely, Tween 80 potentiated AmB toxicity, indicating a synergistic effect.
- A strong correlation was observed between the in vivo toxicity of AmB and its aggregation state in the injected solutions.
- Monomeric AmB solutions demonstrated approximately half the toxicity at 24 hours and six times less toxicity after 1 week compared to Fungizone.
Conclusions:
- Surfactant-mediated control of AmB aggregation state is a viable strategy to reduce its toxicity.
- Formulations promoting AmB monomerization offer a promising approach for safer antifungal therapy.
- Understanding the relationship between AmB aggregation and toxicity is key to developing improved drug delivery systems.