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: B van de Water, T J van Berkel, J Kuiper
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 45 Issue 5 Pg. 971-7 (May 1994) ISSN: 0026-895X [Print] United States
• PMID: 8190111 (Publication Type: Journal Article)

Chemical References

• Adjuvants, Immunologic
• Drug Carriers
• Lipoproteins, LDL
• Phosphatidylethanolamines
• lactosylated LDL
• mifamurtide
• Acetylmuramyl-Alanyl-Isoglutamine

Topics

• Acetylmuramyl-Alanyl-Isoglutamine (analogs & derivatives, metabolism, pharmacology)
• Adjuvants, Immunologic (pharmacology)
• Animals
• Cell Survival (drug effects)
• Drug Carriers (pharmacology)
• In Vitro Techniques
• Kupffer Cells (drug effects, metabolism)
• Lipoproteins, LDL (pharmacology)
• Macrophage Activation (drug effects)
• Male
• Phosphatidylethanolamines (metabolism, pharmacology)
• Rats