Liposomal doxorubicin-induced toxicity: depletion and impairment of phagocytic activity of liver macrophages.
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.
Daemen
T
T
Groningen Institute for Drug Studies, Laboratory of Physiological Chemistry, University of Groningen, The Netherlands.
Hofstede
G
G
Ten Kate
M T
MT
Bakker-Woudenberg
I A
IA
Scherphof
G L
GL
D000818:Animals; D001769:Blood / Q000382:microbiology; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004337:Drug Carriers; D005260:Female; D007728:Kupffer Cells / Q000187:drug effects*; D008081:Liposomes / Q000008:administration & dosage*; D008099:Liver / Q000473:pathology; D008297:Male; D010587:Phagocytosis / Q000187:drug effects*; D051381:Rats
D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin