Prevention of chronic doxorubicin cardiotoxicity in beagles by liposomal encapsulation.

ABSTRACT

Antitumor drugs such as doxorubicin have been encapsulated into liposomes as a means of enhancing activity and reducing toxicity. The present study was initiated to determine whether chronically administered liposome-encapsulated doxorubicin would be less toxic than the free drug. Doxorubicin was prepared in positively charged cardiolipin liposomes, and 1.75 mg/kg was given i.v. to each of five beagles. A second group received the free drug at 1.75 mg/kg. Additional animals received i.v. injections of either doxorubicin-free liposomes or 0.9% NaCl solution. All substances were given at 3-week intervals, and the experiment ended 1 week after the seventh injection (total dose, 12.25 mg/kg). A temporary reduction in food consumption was noted during the first few days after the administration of either form of doxorubicin. The effect was more severe in the dogs given free doxorubicin, and body weight decreased significantly only in this group of animals. Three dogs given free doxorubicin died or were killed before the end of the study because they were in poor condition. Lesions consisting mainly of vacuolization and myofibrillar loss were noted in the hearts of all five dogs given free doxorubicin. The severity of the lesions ranged from 2 to 4 (average, 3.4). In contrast, no abnormalities were found in any of the hearts from dogs given the liposomal doxorubicin. The most obvious general toxic effect caused by administration of free doxorubicin was alopecia, which was entirely prevented when doxorubicin was encapsulated into liposomes. At the dosage regimen utilized, liposomal doxorubicin and free doxorubicin exerted comparable degrees of bone marrow suppression. Thus, liposomal encapsulation of doxorubicin decreased cardiac and other toxic effects elicited by free doxorubicin. Whether this advantage can be translated into effective antineoplastic activity will need further evaluation.