Liposomal doxorubicin-induced toxicity: depletion and impairment of phagocytic activity of liver macrophages.

Abstract

Doxorubicin entrapped within conventional liposomes (200 nm in diameter; lip-Dox) has major toxic effects on liver macrophages of the rat for a considerable period of time following i.v. administration, with respect to both specific phagocytic capacity and cell numbers. At different time-points after injection of lip-Dox or free doxorubicin, radiolabeled, negatively charged, "empty" test liposomes were injected. Phagocytic capacity was determined by isolating the liver macrophages and measuring the amount of macrophage-associated radioactivity. Four subfractions of liver macrophages of different cell-size and with intrinsically different phagocytic capacity were isolated. Twenty-four hours after injection of lip-Dox, the phagocytic capacity of the larger-sized liver macrophages was strongly decreased. The relatively low intrinsic phagocytic capacity of the smaller-sized macrophages was only slightly impaired. Phagocytic capacity after injection of lip-Dox was nearly restored to control values after 14 days. Blood clearance of Klebsiella pneumoniae bacteria after pre-treatment with lip-Dox was strongly decreased. Pre-treatment with the free drug and/or placebo liposomes had no effect on phagocytic and bacterial blood-clearance capacity. A major depletion of the liver macrophage population was observed, as revealed by both macrophage isolation and histology. Only 2 weeks after injection of lip-Dox, the number of cells had returned to that seen in control animals. In view of the important host-defense functions of the liver macrophages, especially in the control of tumor growth and infection, the findings reported here should be taken into consideration when lip-Dox is to be administered in anti-tumor therapy.