Activation of macrophage cytostatic and cytotoxic activity in vitro by liposomes containing a new lipophilic muramyl peptide derivative, MDP-L-alanyl-cholesterol (MTP-CHOL).
The ability of liposomes containing a new lipophilic muramyl peptide derivative, MDP-L-alanyl-cholesterol (MTP-CHOL), to induce peritoneal macrophage cytostatic activity and alveolar macrophage cytotoxic activity toward tumor cell targets in vitro was determined. MTP-CHOL was shown to be efficiently incorporated and subsequently retained in distearoylphosphatidylcholine/phosphatidylserine liposomes (DSPC/PS; 7:3 molar ratio), whereas hydrosoluble muramyl dipeptide (MDP) was rapidly lost due to leakage. Liposomes containing MTP-CHOL were able to stimulate mouse peritoneal macrophage cytostatic activity under conditions where free MDP was without effect. MTP-CHOL incorporated into liposomes was approximately eightfold more effective than liposomes containing entrapped MDP and 7,400-fold more effective than free MDP in inducing rat alveolar macrophage cytotoxic activity. These results provide evidence that the coupling of MDP to a lipophilic molecule, cholesterol, results in the formation of a viable liposome formulation that is a potent inducer of macrophage-mediated antitumor activity.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002788:Cholesterol Esters / Q000138:chemical synthesis / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008081:Liposomes / Q000008:administration & dosage; D008262:Macrophage Activation / Q000187:drug effects*; D012515:Mast-Cell Sarcoma / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains
D002788:Cholesterol Esters; D008081:Liposomes; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C047489:N-acetylmuramyl-alanyl-isoglutamine-alanyl-cholesterol