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首页> 外文期刊>Antiviral chemistry & chemotherapy >Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reducedmitochondrial toxicity.
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Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reducedmitochondrial toxicity.

机译：Nano-NRTIs：巨噬细胞中有效的HIV 1型抑制剂，线粒体毒性降低。

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BACKGROUND: Macrophages serve as a depot for HIV type-1 (HIV-1) in the centralnervous system. To efficiently target macrophages, we developed nanocarriers forpotential brain delivery of activated nucleoside reverse transcriptase inhibitors(NRTIs) called nano-NRTIs.METHODS: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- orPluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI orpoly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogelsdecorated with brain-targeting peptide molecules, specifically binding to theapolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs wereobtained by mixing aqueous solutions of zidovudine 5'-triphosphate or didanosine5'-triphosphate and nanocarriers, followed by freeze-drying. Intracellularaccumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored inmonocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs wasmeasured by a reverse transcriptase activity assay following treatment withnano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells wasassessed by quantitative PCR.RESULTS: Nanogels were efficiently captured by MDMs and demonstrated lowcytotoxicity, and no antiviral activity without drugs. All nano-NRTIsdemonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l,representing a 4.9- to 14-fold decrease in 90% effective drug concentrations ascompared with NRTIs, whereas 50% cytotoxicity effects started at 200× higherconcentrations. Nano-NRTIs with a core-shell structure and decorated withbrain-targeting peptides displayed the highest antiviral efficacy. MitochondrialDNA depletion, a major cause of NRTI neurotoxicity, was reduced threefoldcompared with NRTIs at application of selected nano-NRTIs.CONCLUSIONS: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1in MDMs and showed strong potential as nanocarriers for delivery of antiviraldrugs to macrophages harbouring in the brain.
机译：背景：巨噬细胞在中枢神经系统中充当HIV-1型（HIV-1）的仓库。为了有效地靶向巨噬细胞，我们开发了纳米载体，用于潜在的大脑传递被激活的核苷逆转录酶抑制剂（NRTIs）。方法：由聚乙二醇（PEG）-或Pluronic-聚乙烯亚胺（PEI）可生物降解网络组成的纳米凝胶载体，星形合成并评估了PEG-PEI或聚（酰胺基胺）树枝状聚合物-PEI-PEG树枝状网络，以及用脑靶向肽分子修饰的纳米凝胶，该肽专门结合了载脂蛋白E受体。通过将齐多夫定5'-三磷酸或二肌苷5'-三磷酸的水溶液与纳米载体混合，然后冷冻干燥，获得纳米NRTI。纳米NRTIs的细胞内蓄积，细胞毒性和抗病毒活性进行了监测从单核细胞衍生的巨噬细胞（MDMs）。在用Nano-NRTIs处理后，通过逆转录酶活性测定来测量感染的MDM中的HIV-1病毒活性。结果：纳米凝胶可被MDM有效捕获，并具有低细胞毒性，无药物时无抗病毒活性。所有纳米NRTIs在低至1μmol/ l的药物水平下均表现出对HIV-1的抑制作用，与​​NRTIs相比，90％的有效药物浓度降低了4.9-14倍，而50％的细胞毒性作用始于200x更高的浓度。具有核-壳结构并用脑靶向肽修饰的纳米NRTI表现出最高的抗病毒功效。线粒体DNA消耗是NRTI神经毒性的主要原因，与使用选定的纳米NRTIs相比，与NRTIs相比减少了三倍。结论：纳米NRTIs在MDM中显示出对HIV-1的有前途的抗病毒功效，并显示出将纳米载体传递抗病毒药物的强大潜力。藏在大脑中。

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