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 polyguany lic acid (PolyG) is specifically internalized by macrophages through scaven ger receptor (SCR)-mediated endocytosis. Macrophages activated by PolyG-MDP displayed about 20-fold higher cytotoxic activity against nonmacrophage tu mor cells compared to that elicited by free MDP. The PolyG-MDP was found to trigger the secretion of higher levels of interleukin-6, interleukin-1 alp ha, TNF-alpha, and nitric oxide in comparison to free MDP. Addition of anti bodies 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 a nd antisense oligonucleotides to macrophages, (C) 2000 Academic Press.