Selective activation of antitumor activity of macrophages by the delivery of muramyl dipeptide using a novel polynucleotide-based carrier recognized by scavenger receptors.
We have shown that muramyl dipeptide (MDP) conjugated to a 10-mer polyguanylic acid (PolyG) is specifically internalized by macrophages through scavenger receptor (SCR)-mediated endocytosis. Macrophages activated by PolyG-MDP displayed about 20-fold higher cytotoxic activity against nonmacrophage tumor cells compared to that elicited by free MDP. The PolyG-MDP was found to trigger the secretion of higher levels of interleukin-6, interleukin-1alpha, TNF-alpha, and nitric oxide in comparison to free MDP. Addition of antibodies directed against IL-6 and TNF-alpha to macrophage culture completely abrogated the tumoricidal response of PolyG-MDP, indicating that these two cytokines are primarily responsible for bioefficacy. This general approach of PolyG as a vehicle may find wide application in the delivery of genes and antisense oligonucleotides to macrophages.
Srividya
S
S
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
Roy
R P
RP
Basu
S K
SK
Mukhopadhyay
A
A
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004337:Drug Carriers; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D011068:Poly G / Q000008:administration & dosage / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004337:Drug Carriers; D007375:Interleukin-1; D015850:Interleukin-6; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; D011068:Poly G; D009569:Nitric Oxide; D000119:Acetylmuramyl-Alanyl-Isoglutamine