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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes.

Doxorubicin possesses high affinity for binding to cardiolipin. We have utilized these properties in preparing stable liposomes of doxorubicin and cardiolipin with a net positive charge. Doxorubicin liposomes were formed by using 11.2 mumol of drug, 5.6 mumol of cardiolipin, 28.5 mumol of phosphatidylcholine, 19.5 mumol of cholesterol, and 11.1 mumol of stearylamine. These liposomes were sonicated for 90 min at 37 degrees followed by extensive dialysis against buffer. The pharmacological, toxicological, and therapeutic effects of doxorubicin entrapped in cardiolipin liposomes were compared with those of free doxorubicin in mice. At a dose of 4 mg/kg i.v., the peak cardiac concentration was achieved in 30 min following free doxorubicin administration, the value being 8.1 micrograms/g. The peak cardiac concentration with doxorubicin in cardiolipin liposomes was obtained at 5 min with a value of 2.8 micrograms/g of tissue. The cardiac concentration X time values for free doxorubicin for the 24-hr period of observation were 55.1 micrograms X hr/g, whereas it was only 7.8 micrograms X hr/g with the drug entrapped in cardiolipin liposomes. Compared to free drug, the liposomal entrapped doxorubicin significantly reduced the histopathological lesions in cardiac tissue of mice at a dose of 15 mg/kg as determined by electron microscopy. The nadir of peripheral white blood cell counts in mice with free drug, 6 mg/kg, was observed on Day 3 which was 50% of control, whereas with liposomal encapsulated drug it was reduced only 23% on Day 7. Doxorubicin in cardiolipin liposomes demonstrated enhanced chemotherapeutic potential against murine ascitic P388 leukemia with a 144% increased life span compared to 55% increased life span with free drug at a dose of 7.5 mg/kg on Days 1, 3, and 7. We conclude that doxorubicin liposomes developed in these studies possess improved therapeutic action as demonstrated by their ability to reduce the toxicity of the drug substantially.[1]


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