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Liposomal hamycin: reduced toxicity and improved antifungal efficacy in vitro and in vivo
R T Mehta1, T J McQueen, A Keyhani
1Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
Hamycin has been used to treat a variety of yeast and other fungal infections by oral, topical, and intraperitoneal routes. However, its parenteral use has been reported to be associated with high toxicity. Multilamellar liposomes composed of dimyristoyl phosphatidyl choline, dimyristoyl phosphatidyl glycerol, and various amounts of cholesterol were used as drug carriers for hamycin. The antifungal activity of hamycin was maintained after liposome encapsulation (MIC range, 0.6-1.2 micrograms/ml), and toxicity was reduced in vitro and in vivo as the concentration of cholesterol was increased to an appropriate ratio. Mice were treated with various doses of free or liposomal hamycin 2 days after infection. Although free drug did not significantly improve survival, liposomal hamycin at an equivalent dose (0.6 mg/kg) increased the survival from 18 to 38 days. Higher doses (1.2 and 1.8 mg/kg) showed further improvement in survival and reduction in numbers of colony-forming units in the kidneys. Liposome encapsulation resulted in improved therapeutic index of hamycin.
Insights
Liposome encapsulation improved hamycin's antifungal efficacy and reduced toxicity. This novel drug delivery system enhanced survival rates in mice infected with fungi, offering a safer therapeutic option.
Area of Science:
- Pharmaceutical Sciences
- Mycology
- Drug Delivery Systems
Background:
- Hamycin is an antifungal agent effective against various fungal infections.
- Parenteral administration of hamycin is linked to significant toxicity.
- Liposomes offer a potential strategy to improve drug delivery and reduce toxicity.
Purpose of the Study:
- To evaluate the efficacy and safety of hamycin encapsulated in multilamellar liposomes.
- To determine if liposome encapsulation can maintain antifungal activity while reducing hamycin's toxicity.
- To assess the therapeutic index of liposomal hamycin compared to free hamycin.
Main Methods:
- Hamycin was encapsulated in multilamellar liposomes composed of dimyristoyl phosphatidyl choline, dimyristoyl phosphatidyl glycerol, and varying cholesterol concentrations.
- Antifungal activity was assessed by determining the minimum inhibitory concentration (MIC).
- In vitro and in vivo toxicity studies were conducted.
- Survival rates and kidney colony-forming units were evaluated in a mouse model of fungal infection.
Main Results:
- Liposome encapsulation maintained hamycin's antifungal activity (MIC range, 0.6-1.2 µg/ml).
- Increased cholesterol concentration in liposomes reduced hamycin's toxicity both in vitro and in vivo.
- Liposomal hamycin significantly improved survival in infected mice compared to free hamycin.
- Higher doses of liposomal hamycin further enhanced survival and reduced fungal burden in kidneys.
Conclusions:
- Liposome encapsulation is an effective strategy to improve the therapeutic index of hamycin.
- Cholesterol-enriched liposomes enhance the safety profile of hamycin for parenteral use.
- Liposomal hamycin demonstrates promising potential for treating systemic fungal infections with reduced toxicity.