Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

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Abstract
Doxorubicin-loaded, glutaraldehyde-treated murine erythrocytes, once reinjected into circulation, are rapidly taken up by liver and lungs and behave as an organtargeted, slow delivery system for the encapsulated drug. The antitumor activity of encapsulated doxorubicin (former generic name, adriamycin) was compared with that of the free drug in a murine hepatic pulmonary tumor model. This was obtained by intrasplenic injection of L1210 lymphoma cells followed by splenectomy. Different schedules of treatment of tumor hearing mice with erythrocyte-encapsulated or free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin proved to be i.v. bolus administration on the day of splenectomy. Under these conditions, the dose producing 50% inhibition of metastatic growth in the liver, as measured by inhibition of 5-[125I]iodo-2''-deoxyuridine uptake 9 days after tumor induction, was 6.3 mg/kg for free doxorubicin and 0.48 mg/kg for the encapsulated drug. In these conditions pulmonary tumor development was even more efficiently prevented by encapsulated doxorubicin as compared with the free drug. The values of the therapeutic index (TI), defined as the ration between the maximal tolerated dose (LD10) and the minimal effective dose (ED90, producing 90% inhibition of liver metastatic growth), were 4.2 and 1.8 for encapsulated and free doxorubicin, respectively.