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 liver

A tumor model designed to assess liposome-mediated drug delivery to liver h as been used in an attempt to better understand the mechanism of activity o f liposomal mitoxantrone, a liposomal anticancer drug formulation that appe ars to be uniquely effective in treating this tumor model. Reductions in li posomal mitoxantrone accumulation in the liver were achieved either by use of poly(ethylene)glycol (PEG)-modified lipids or by methods designed to dep lete liver phagocytes, a method referred to as hepatic mononuclear phagocyt ic system (MPS) blockade. A 2-fold reduction in mitoxantrone delivery to th e liver was obtained using a mitoxantrone! formulation with PEG-modified li pids, and a 3-fold reduction was obtained when liposomal mitoxantrone was g iven to animals pretreated to induce hepatic MPS blockade. Results demonstr ate that the liposomal mitoxantrone formulation prepared with PEG-modified lipids was significantly less active than the formulations that did not con tain PEG lipids, with median survival times of 17 days and 100% 60-day surv ival, respectively, In contrast, hepatic MPS blockade had no effect on the therapeutic activity of 1,2-dimyristoyl phosphatidylcholine/cholesterol (DM PC/Chol) mitoxantrone (100% 60-day survival). These data suggest that the h epatic MPS does not play a role in mediating the therapeutic activity of DM PC/Chol mitoxantrone in the treatment of liver localized disease. Results w ith formulations prepared with a PEG-stabilized surface, however, suggest t hat nonspecific methods to decrease liposome cell interactions inhibit the therapeutic activity of DMPC/Chol mitoxantrone.