Division of Infectious Diseases, Department of Medicine , David Geffen School of Medicine at UCLA , Los Angeles , California , United States.
Department of Chemistry and Biochemistry , University of California , Los Angeles , California , United States.
Bioconjug Chem. 2019 Aug 21;30(8):2216-2227. doi: 10.1021/acs.bioconjchem.9b00451. Epub 2019 Jul 16.
"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1.
“穹窿”是普遍表达的内源性核糖核蛋白纳米颗粒，具有潜在的靶向药物递送的应用价值。在这里，我们发现重组人穹窿纳米颗粒很容易被某些关键的人外周血单核细胞（PBMC），主要是树突状细胞、单核细胞/巨噬细胞和活化的 T 细胞吞噬。由于这些细胞类型是人类免疫缺陷病毒 1（HIV-1）感染的主要靶标，我们研究了重组人穹窿用于靶向递送抗逆转录病毒药物的用途。我们对三种不同的抗逆转录病毒药物，齐多夫定、替诺福韦和艾维雷格韦，进行了化学修饰，以直接连接到穹窿上。在感染实验中进行测试，药物连接的穹窿抑制了 PBMC 中 HIV-1 的感染，与游离药物的活性相当，表明在 HIV-1 易感细胞的细胞质中进行了穹窿的递送和药物的释放。通过穹窿纳米颗粒缀合物递送功能性药物的能力表明它们在针对 HIV-1 的靶向药物递送中有潜在的应用价值。
