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Influence of Lipid Composition on the Antitumor Activity Exerted by Doxorubicin-containing Liposomes in a Rat Solid Tumor Model

Department of Pharmaceutics, Subfaculty of Pharmacy, State University of Utrecht, Croesestraat 79, 3522 AD Utrecht [G. S., D. J. A. C.]; Laboratory of Physiological Chemistry, State University, Groningen [F. H. R.]; and Laboratory for Pathology, National Institute of Public Health and Environmental Hygiene (RIVM), Bilthoven [P. A. S., W. H. J.], The Netherlands

The effect of changes in lipid composition on the antitumor activity of doxorubicin (DXR)-containing liposomes was studied in immunoglobulin solid immunocytoma-bearing Lou/M Wsl rats. Rats bearing a tumor with a diameter between 20 and 30 mm were treated i.v. with 2 mg/kg free DXR or different DXR-containing liposome types for 5 consecutive days followed by one injection more at day 11 after start of therapy. A similar pattern of tumor regression was observed for free DXR and DXR entrapped in "fluid" liposome types. However, DXR entrapped in "solid" liposome types expressed an antitumor activity which was significantly delayed; during the first 3 days after start of therapy solid DXR-containing liposomes were less effective in inducing antitumor activity than fluid DXR-containing liposomes.

In order to gain more insight into the mode of action of DXR-containing liposomes, one of the solid liposome types [composed of distearoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and cholesterol (chol)] was compared with one of the fluid liposome types [composed of egg phosphatidylcholine, phosphatidylserine, and chol] with respect to distribution and integrity in vivo. Results obtained after i.v. administration of [³H]inulin-labeled vesicles to tumor-bearing animals suggested that a differential liposome uptake by the tumor was not relevant for the explanation of the delayed antitumor effect. To monitor the structural integrity of liposomes after i.v. injection, the liposomes were double radiolabeled with [³H]inulin as a marker of the aqueous phase and cholesteryl [¹⁴C]oleate as a marker of the lipid phase. The bilayer structure of both liposome types remained intact during their presence in the blood compartment. Intact liposomes were taken up primarily by liver and spleen with subsequent degradation of the liposome structure. The degradation rate appeared to be dependent on the lipid composition of the liposomal membranes; phosphatidylcholine/phosphatidylserine/chol liposomes were degraded much faster than distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol/chol liposomes. The difference in degradation rate was manifested more clearly in the spleen than in the liver. In vitro investigations on uptake and processing of liposomes by liver macrophages indicated that the difference in degradation rate between liver and spleen was caused by intrahepatic reutilization of [¹⁴C]oleate liberated from the liposome structures.

Correlation of the relatively slow degradation of the solid liposomes with the delayed antitumor activity exhibited by these liposomes in vivo suggests that the antitumor activity exerted by DXR-containing liposomes in vivo is dependent on the rate of degradation of the liposome structure within mononuclear phagocytes of the reticuloendothelial system.

¹ To whom requests for reprints should be addressed.

Received 6/20/86. Revised 12/22/86. Accepted 3/20/87.

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