Investigation of the role of mononuclear phagocytes in the transportation of doxorubicin-containing liposomes into a solid tumor.
The present paper is concerned with the question whether cells of the mononuclear phagocyte system (MPS) function as a transport system for doxorubicin (DXR)-containing liposomes into solid tumors. The investigations were performed in solid IgM immunocytoma bearing Lou/M Wsl rats. In this tumor system macrophage accumulation was observed during DXR and cisplatin induced tumor regression. Tumor-bearing rats were treated i.v. with 1 mg/kg DXR (either free or entrapped in liposomes) for 4 consecutive days. Changes in the cellular composition of the tumor were studied by histology and cytology comparing free and liposomal DXR treatment. Therapy with DXR-liposomes (lip DXR) induced macrophage accumulation similar to free DXR. No differences in cellular changes in the tumor between both types of treatment were found. The DXR-content of tumor-associated cells was measured at various times during treatment with free or lip DXR by means of flow cytometry. Most DXR-fluorescence was associated with dead cells and cellular debris. No clear-cut differences in DXR-content were found between macrophages isolated from tumors of free DXR treated animals and those isolated from lip DXR treated animals. In order to investigate whether DXR-liposomes are taken up by tumor tissue (either via macrophages or directly by the tissue itself), [3H]inulin-labeled DXR-liposomes were administered to tumor-bearing rats. The distribution of radiolabeled lip DXR in non-treated rats was compared with that in rats which were pretreated with non-radiolabeled lip DXR to induce macrophage accumulation. In both untreated and pretreated animals most of the administered 3H-dose was recovered in liver and spleen. Only a minor fraction was recovered from the tumor and other tissues. This fraction was not higher than that obtained when a comparable amount of free [3H]inulin was injected. In conclusion, this study suggests that DXR-liposomes do not enter the solid IgM immunocytoma, even when during therapy macrophages pass the endothelial barrier. Therefore, it is unlikely that macrophage-mediated transportation of DXR-liposomes into the tumor is involved in the mechanism of tumor regression induced by liposome-entrapped DXR.
Department of Pharmaceutics, Subfaculty of Pharmacy, State University, Utrecht, The Netherlands.
G
G
Storm
H J
HJ
Van Gessel
P A
PA
Steerenberg
P A
PA
Speth
F H
FH
Roerdink
J
J
Regts
M
M
Van Veen
W H
WH
De Jong
D000818:Animals; D001692:Biological Transport; D004317:Doxorubicin / Q000008:administration & dosage*; D005434:Flow Cytometry; D007963:Leukocytes, Mononuclear; D008081:Liposomes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D008856:Microscopy, Fluorescence; D010586:Phagocytes / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D008081:Liposomes; D004317:Doxorubicin