Targeting antiviral nucleotide analogues to macrophages
Targeting antiviral nucleotide analogues to macrophages
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DOI：
10.1002/jlb.62.1.133
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发表时间：
1997-07-01
影响因子：
5.5
通讯作者：
DeFlora, A
中科院分区：
文献类型：
--
作者：
Magnani, M;Rossi, L;DeFlora, A
巨噬细胞是人类免疫缺陷病毒1型(HIV-1)感染的重要靶细胞，我们开发了一种选择性递送磷酸化核苷类似物到这些吞噬细胞的药物靶向系统，该系统基于将磷酸化药物包裹到自体红细胞中并随后选择性地修饰其膜以促进巨噬细胞识别和吞噬的可能性，靶向递送磷酸化核苷类似物到人、猫和小鼠巨噬细胞可更有效地抑制HIV-1、猫免疫缺陷病毒和LP-BM5病毒的感染性，体内给药比给予相应的核苷类似物更有效。3‘-二脱氧胞苷5’-三磷酸(DdCTP)被包裹在自体红细胞中，可减少LP-BM5感染小鼠的感染性和疾病进展。此外，同时给予AZTodC可产生相加的抗病毒作用，利用红细胞作为药物靶向系统的可能性有助于新的抗病毒核苷类似物的设计、合成和递送。作为这些新药的原型，制备了di-(thymidine-3‘-azido-2’，3‘-dideoxy-D-riboside)-5’-5‘-p(1)-p(2)-pyrophosphate(AZTp(2)AZT)。尽管这种药物在溶液中具有与AZT相同的抗病毒活性，但当被囊化到红细胞中时，它在抑制人、猫和小鼠免疫缺陷病毒的传染性方面的效率要高出数倍，因此，选择性地将抗病毒药物输送到巨噬细胞的药物靶向系统的可用性为新药和新的联合抗病毒疗法的开发提供了额外的可能性。
Macrophages are important target cells for human immunodeficiency virus type 1 (HIV-1) infection, 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 phosphorylated drugs into autologous erythrocytes and on the subsequent selective modification of their membranes to promote macrophage recognition and phagocytosis, Targeted delivery of phosphorylated nucleoside analogues to human, feline, and murine macrophages inhibits the infectivity of HIV-1, feline immunodeficiency virus, and LP-BM5 viruses more efficiently than the administration of the corresponding nucleoside analogues, In vivo administration of 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) encapsulated into autologous erythrocytes to LP-BM5-infected mice was found to reduce infectivity and disease progression, Furthermore, the simultaneous administration of AZT oi ddC produced additive antiviral effects, The possibility of using red cells as drug targeting systems was useful for the design, synthesis, and delivery of new antiviral nucleoside analogues, As a prototype of these new drugs, di-(thymidine-3'-azido-2',3'-dideoxy-D-riboside)-5'-5'-p(1)-p(2)-pyrophosphate (AZTp(2)AZT) 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 inhibiting the infectivity of human, feline, and murine immunodeficiency viruses, Thus, the availability of a drug targeting system for the selective delivery of antivirals to macrophages offers an additional possibility for the development of new drugs and of new combination antiviral therapies.