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Liposomal Doxorubicin‐induced Toxicity: Depletion And Impairment Of Phagocytic Activity Of Liver Macrophages

T. Daemen, G. Hofstede, M. ten Kate, I. A. Bakker-Woudenberg, G. Scherphof
Published 1995 · Medicine

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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. © 1995 Wiley‐Liss, Inc.
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