RED-BLOOD-CELLS MEDIATED DELIVERY OF 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE TO PRIMARY MACROPHAGES - EFFICIENCY, METABOLISM AND ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS OR HERPES-SIMPLEX VIRUS

Red blood cells (RBC) may act as selective carriers of drugs to macrop hages, an important reservoir of viruses such as human immunodeficienc y virus (HIV) and herpes simplex virus type 1 (HSV-1). We therefore as sessed the incorporation of 9-(2-phosphonylmethoxyethyl)adenine (PMEA, a potent inhibitor of HIV and HSV-1) into RBC, its delivery to macrop hages and its activity against HIV or HSV-1. Loading of PMEA in artifi cially aged opsonized RBC affords significant levels of intracellular PMEA. RBC metabolize PMEA to its active congener PMEA-diphosphate, alt hough with low efficiency. Exposure of macrophages to RBC-encapsulated PMEA inhibits the replication of both HIV and HSV-1 (about 90% inhibi tion at the highest RBC:macrophages ratios) even if RBC were removed b efore virus challenge. By contrast, the antiviral activity of free PME A removed before virus challenge was irrelevant at concentrations up t o 150-fold higher than the 50% effective concentration (EC(50)) Finall y, the antiviral effect of RBC-encapsulated PMEA correlates with PMEA levels in macrophages about 500-fold higher than those achieved by fre e PMEA (at concentrations 10-fold higher than the EC(50)). The efficac y of RBC-mediated delivery to macrophages of PMEA (and perhaps of comp ounds with shorter intracellular half-lives) warrants further studies in infectious diseases involving phagocytizing cells as main targets o f the pathogen. (C) 1997 Elsevier Science B.V.