ACTIVATION OF RAT KUPFFER CELLS TO TUMORICIDAL CELLS BY THE IMMUNOMODULATOR MURAMYL TRIPEPTIDE-PHOSPHATIDYLETHANOLAMINE INCORPORATED INTO THE NOVEL DRUG CARRIER LACTOSYLATED LOW-DENSITY-LIPOPROTEIN

Lactosylated low density lipoprotein (lac-LDL) is a potential carrier for the site-specific delivery of lipophilic drugs to liver macrophage s (Kupffer cells). In the present study we evaluated the application o f lac-LDL as a carrier to target the immunomodulator muramyl tripeptid e-phosphatidylethanolamine (MTP-PE) to rat Kupffer cells, to specifica lly activate these cells to tumor-killing cells. The drug carrier I-12 5-labeled lac-LDL interacted with a galactose-specific recognition sys tem on isolated rat Kupffer cells. The in vitro association of I-125-l ac-LDL at 37 degrees was maximal after 20 min, whereas degradation of I-125-lac-LDL was observed after a lag period of 10 min. Cultured rat Kupffer cells were activated after incubation with MTP-PE incorporated into lac-LDL. Lac-LDL-MTP-PE induced a 2-fold increase in the amount of newly synthesized proteins secreted by Kupffer cells. Lac-LDL-MTP-P E induced a concentration-dependent increase in the cytostatic and cyt olytic activities of Kupffer cells towards tumor cells (B16F10 melanom a cells) in vitro. Treatment of rats with lac-LDL-MTP-PE also resulted in dose-dependent activation of Kupffer cells to tumoricidal cells, w hereas the drug carrier alone had only a minor effect on this activity of Kupffer cells. The present data show that lac-LDL is an effective carrier for the delivery of the lipophilic immunomodulator MTP-PE to r at Kupffer cells. The specific activation of Kupffer cells to tumorici dal cells by lac-LDL-MTP-PE may be beneficial for the treatment of liv er metastases.