SCAVENGER RECEPTOR-MEDIATED DELIVERY OF ANTISENSE MINI-EXON PHOSPHOROTHIOATE OLIGONUCLEOTIDE TO LEISHMANIA-INFECTED MACROPHAGES - SELECTIVEAND EFFICIENT ELIMINATION OF THE PARASITE

Targeted delivery of a 17-mer antisense phosphorothioate oligodeoxyrib onucleotide, complementary to the common 5'-end of every mRNA of the p arasite cells, to the phagolysosomes of cultured murine macrophages in fected with Leishmania mexicana amazonensis selectively and efficientl y eliminated the parasite cells without causing any detectable harm to the host cells. The antisense mini-exon oligonucleotide (ASM) was enc apsulated into liposomes coated with maleylated bovine serum albumin ( MESA), the artificial ligand for macrophage scavenger receptors. MBSA- coating of the liposomes allowed specific binding of the liposomes to the macrophages, their receptor-mediated uptake, and subsequent degrad ation of tile liposomes inside macrophage phagolysosomes to release AS M. When incubated with Leishmania-infected macrophages, MBSA-liposome- encapsulated ASM (10 mu M) was able to kill >90% of the parasites with in 5 hr as compared with 20% killing within this time period by free A SM. Oligonucleotides with complementary nucleotide sequence or with th e same base composition as ASM but scrambled sequence had no antileish manial effect under the conditions of the assay. This study reflects t he efficacy of scavenger-receptor-mediated delivery of antisense phosp horothioate oligos in killing intraphagolysosomal pathogens. Copyright (C) 1997 Elsevier Science Inc.