Red blood cells as advanced drug delivery systems for antiviral nucleoside analogues.

Abstract

A broad family of nucleoside analogues are able to inhibit the infectivity and replication of several HIV-1 strains in vitro.1,2 The most popular of these compounds, AZT (3’-azido-3’-deoxythymidine), has been approved in the U.S.A. as a prescription drug since 1987. Although AZT reduces morbidity and mortality associated with severe HIV infection, several toxic effects have limited its long-term administration. 2’,3’-Dideoxycytidine (ddCyd) was subsequently tested clinically3 as potential therapeutic agent. Again ddCyd has shown immunological and virologic improvement in AIDS patients but most individuals developed dose-limiting toxic effects. The same applies to 2’,3’-dideoxyinosine (ddl).4,5 In an attempt to overcome the problem of nucleoside analogue toxicity and to increase their half-life in circulation we have previously synthesized 2’,3’-dideoxycytidine-5’-phosphate (ddCMP) as a prodrug, encapsulated it in human erythrocytes by a procedure of hypotonic hemolysis and resealing, and found that it is dephosphorylated by endogenous pyrimidine nucleotidases and subsequently released by the cells as ddCyd.6 By this way the prodrug is confined within the erythrocytes so that its toxicity is strongly reduced and its delivery is slow enough to ensure a long-lasting plasma concentration.? Unfortunately this drug delivery system does not solve several other problems of nucleoside analogue efficacy. In fact, to be pharmacologically useful dideoxynucleosides must be phosphorylated to 5’-triphosphate by cellular kinases.1,2 Different cell types within the same species have different abilities to phosphorylate these compounds, furthermore, other drugs can potentiate or reduce the activity of these nucleoside analogues by interfering with their metabolism directly or indirectly.8 Macrophages, which are known to be important hosts for HIV-1 with a key role in the propagation of virus as well as in the pathogenesis of AIDS, has low phosphorylating activities.