Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity.

Abstract

Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.