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Kupffer Cells Do Not Play a Role in Governing the Efficacy of Liposomal Mitoxantrone Used to Treat a Tumor Model Designed to Assess Drug Delivery to Liver¹

Department of Advanced Therapeutics, British Columbia Cancer Agency, Vancouver, British Columbia, V5Z 4E6 Canada [H. J. L., D. M., N. L. M., S. J., M. B. B.]; Departments of Pathology and Laboratory Medicine [H. J. L., M. B. B.] and Pharmacology and Therapeutics [T. D. M.], University of British Columbia, Vancouver, British Columbia, V6T 1Z3 Canada; School of Dentistry, University of California, San Francisco, California 94143 [G. Z.]; and Biogen, Inc., Cambridge, Massachusetts 02142 [M. J. P.]

ABSTRACT

A tumor model designed to assess liposome-mediated drug delivery to liver has been used in an attempt to better understand the mechanism of activity of liposomal mitoxantrone, a liposomal anticancer drug formulation that appears to be uniquely effective in treating this tumor model. Reductions in liposomal mitoxantrone accumulation in the liver were achieved either by use of poly(ethylene)glycol (PEG)-modified lipids or by methods designed to deplete liver phagocytes, a method referred to as hepatic mononuclear phagocytic system (MPS) blockade. A 2-fold reduction in mitoxantrone delivery to the liver was obtained using a mitoxantrone formulation with PEG-modified lipids, and a 3-fold reduction was obtained when liposomal mitoxantrone was given to animals pretreated to induce hepatic MPS blockade. Results demonstrate that the liposomal mitoxantrone formulation prepared with PEG-modified lipids was significantly less active than the formulations that did not contain PEG lipids, with median survival times of 17 days and 100% 60-day survival, respectively. In contrast, hepatic MPS blockade had no effect on the therapeutic activity of 1,2-dimyristoyl phosphatidylcholine/cholesterol (DMPC/Chol) mitoxantrone (100% 60-day survival). These data suggest that the hepatic MPS does not play a role in mediating the therapeutic activity of DMPC/Chol mitoxantrone in the treatment of liver localized disease. Results with formulations prepared with a PEG-stabilized surface, however, suggest that nonspecific methods to decrease liposome cell interactions inhibit the therapeutic activity of DMPC/Chol mitoxantrone.