Targeting antiviral nucleotide analogues to macrophages

Abstract: Macrophages are important target cells for human immunodeficiency virus type 1 (HIV-1) infec-tion. We have developed a drug targeting system for the selective delivery of phosphorylated nucleoside analogues to these phagocytosing cells. This system is based on the possibility of encapsulating the phos-phorylated drugs into autologous erythrocytes and on the subsequent selective modification of their mem-branes to promote macrophage recognition and phago-cytosis. Thrgeted delivery ofphosphorylated nucleoside analogues to human, feline, and murine macrophages inhibits the infectivity of 11W-i, feline immunodeficien-cy virus, and LP-BM5 viruses more efficiently than the administration of the corresponding nucleoside ana-logues. In vivo adminiatration of 2’,3’-dideoxycytidine 5’-triphosphate (ddCTP) encapsulated into autologous erytbrocytes to LP-BM5-infected mice was found to reduce infectivity and disease progression. Further-more, the simultaneous ailminiatration ofAZT or ddC produced additive antiviral effects. The possibility of using red cells as drug targeting systems was useful for the design, synthesis, and delivery ofnew antiviral nu-cleoside analogues. As a prototype ofthese new drugs, di-(thymidine-3’-azido-2’,3’-dideoxy-i-riboside)-5’-5’-p’-p2-pyrophosphate (AZTp2AZT) was prepared. Although this drug in solution has the same antiviral activity as AZT, when administered encapsulated into erythrocytes it was several times more efficient in in-bibiting the infectivity of human, feline, and murine immunodeficiency viruses. Thus, the availability of a drug targeting system for the selective delivery of antivfraI to macrophages offers an additional possi-bility for the development of new drugs and of new combination antiviral therapies. J. Leukoc. Biol. 62