title: 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.
abstract: Red blood cells (RBC) may act as selective carriers of drugs to macrophages, an important reservoir of viruses such as human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1). We therefore assessed the incorporation of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent inhibitor of HIV and HSV-1) into RBC, its delivery to macrophages and its activity against HIV or HSV-1. Loading of PMEA in artificially aged opsonized RBC affords significant levels of intracellular PMEA. RBC metabolize PMEA to its active congener PMEA-diphosphate, although with low efficiency. Exposure of macrophages to RBC-encapsulated PMEA inhibits the replication of both HIV and HSV-1 (about 90% inhibition at the highest RBC:macrophages ratios) even if RBC were removed before virus challenge. By contrast, the antiviral activity of free PMEA removed before virus challenge was irrelevant at concentrations up to 150-fold higher than the 50% effective concentration (EC50). Finally, the antiviral effect of RBC-encapsulated PMEA correlates with PMEA levels in macrophages about 500-fold higher than those achieved by free PMEA (at concentrations 10-fold higher than the EC50). The efficacy of RBC-mediated delivery to macrophages of PMEA (and perhaps of compounds with shorter intracellular half-lives) warrants further studies in infectious diseases involving phagocytizing cells as main targets of the pathogen.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Italy.
authors.forename: C F
authors.initials: CF
authors.lastname: Perno
authors.forename: N
authors.initials: N
authors.lastname: Santoro
authors.forename: E
authors.initials: E
authors.lastname: Balestra
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
authors.forename: A
authors.initials: A
authors.lastname: Cenci
authors.forename: G
authors.initials: G
authors.lastname: Lazzarino
authors.forename: D
authors.initials: D
authors.lastname: Di Pierro
authors.forename: B
authors.initials: B
authors.lastname: Tavazzi
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: E
authors.initials: E
authors.lastname: Garaci
authors.forename: S
authors.initials: S
authors.lastname: Grimaldi
authors.forename: R
authors.initials: R
authors.lastname: Caliò
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004337:Drug Carriers; D004912:Erythrocytes / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008264:Macrophages / Q000821:virology*; D063065:Organophosphonates; D014709:Vero Cells
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004337:Drug Carriers; D063065:Organophosphonates; C053001:adefovir; D000225:Adenine