title: Activation of rat Kupffer cells to tumoricidal cells by the immunomodulator muramyl tripeptide-phosphatidylethanolamine incorporated into the novel drug carrier lactosylated low density lipoprotein.
abstract: Lactosylated low density lipoprotein (lac-LDL) is a potential carrier for the site-specific delivery of lipophilic drugs to liver macrophages (Kupffer cells). In the present study we evaluated the application of lac-LDL as a carrier to target the immunomodulator muramyl tripeptide-phosphatidylethanolamine (MTP-PE) to rat Kupffer cells, to specifically activate these cells to tumor-killing cells. The drug carrier 125I-labeled lac-LDL interacted with a galactose-specific recognition system on isolated rat Kupffer cells. The in vitro association of 125I-lac-LDL at 37 degrees was maximal after 20 min, whereas degradation of 125I-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-PE induced a concentration-dependent increase in the cytostatic and cytolytic activities of Kupffer cells towards tumor cells (B16F10 melanoma cells) in vitro. Treatment of rats with lac-LDL-MTP-PE also resulted in dose-dependent activation of Kupffer cells to tumoricidal cells, whereas 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 rat Kupffer cells. The specific activation of Kupffer cells to tumoricidal cells by lac-LDL-MTP-PE may be beneficial for the treatment of liver metastases.
authors.affiliation: Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, Sylvius Laboratory, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van de Water
authors.forename: T J
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: J
authors.initials: J
authors.lastname: Kuiper
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000494:pharmacology*; D066298:In Vitro Techniques; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D010714:Phosphatidylethanolamines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
chemical_list: D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D008077:Lipoproteins, LDL; D010714:Phosphatidylethanolamines; C027759:lactosylated LDL; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine