Induction of macrophage antitumor activity by acetylated low density lipoprotein containing lipophilic muramyl tripeptide.
A method has been developed for the selective delivery of lipophilic immunomodulators to macrophages, which results in the induction of antitumor activity. This method utilizes exhaustively acetylated low density lipoprotein (acetyl-LDL) to deliver the lipophilic immunomodulator, muramyl tripeptide phosphatidylethanolamine (MTP-PtdEtn; amide composed of N-acetylmuramyl-L-alanyl-D-isoglutamyl-L-alanine and dipalmitoyl phosphatidylethanolamine) to macrophages (M phi) by means of a scavenger lipoprotein receptor pathway. The binding of acetyl-LDL:MTP-PtdEtn to M phi showed specificity since minimal competition was observed in the presence of excess native LDL or phosphatidylcholine/cholesterol liposomes. Additional binding studies showed that acetyl-LDL may serve as a suitable delivery vehicle to a wide variety of M phi in different stages of activation. Cytostatic and tumoricidal activities by thioglycolate-elicited M phi against two tumor cell lines were examined in vitro following incubation with the acetyl-LDL:MTP-PtdEtn complex. Cytostatic activity against B16F10 melanoma cells was induced after the incubation of thioglycolate-elicited M phi with a minimum of 25 micrograms of acetyl-LDL protein containing 2.5 micrograms of bound MTP-PtdEtn (approximately equal to 40 molecules per particle of acetyl-LDL). The induction of cytostasis was not affected by liposome bilayers, which were also endocytosed by the M phi. In addition, tumoricidal activity against P815 mastocytoma cells was demonstrated at a 40:1 effector-to-target ratio using 18 micrograms of the acetyl-LDL:MTP-PtdEtn complex containing 3.6 micrograms of MTP-PtdEtn (approximately equal to 80 molecules per particle). These studies describe a method for the induction of antitumor activity by use of a chemically modified serum component, acetyl-LDL, to direct lipophilic immunomodulators to M phi.
Shaw
J M
JM
Department of Animal Sciences, University of Illinois, Urbana 61801.
Futch
W S
WS
Schook
L B
LB
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000276:immunology*; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D008077:Lipoproteins, LDL; D010714:Phosphatidylethanolamines; C032629:acetyl-LDL; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine