Core-shell nanoparticles for targeted and combination antiretroviral activity in gut-homing T cells.
Core-shell nanoparticles for targeted and combination antiretroviral activity in gut-homing T cells.
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DOI：
10.1016/j.nano.2018.06.005
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Woodrow KA
中科院分区：
文献类型：
--
作者：
Cao S;Jiang Y;Zhang H;Kondza N;Woodrow KA
HIV感染的一个主要避难所是肠道相关淋巴组织（GALT）。α4β7整联蛋白肠道归巢受体是病毒储库的一个有前途的治疗靶点，因为它导致感染细胞迁移到GALT并促进HIV感染。在这里，我们开发了一种核壳纳米颗粒，将α4β7单克隆抗体（mAb）作为双功能配体，用于选择性地将蛋白酶抑制剂（PI）靶向GALT中的肠道归巢T细胞，同时阻断HIV感染。我们的纳米颗粒显著降低了PI的细胞毒性，并增强了其与α4β7 mAb组合的体外抗病毒活性。我们证明了我们的纳米载体在人T细胞系和从猕猴回肠分离的原代细胞中的靶向功能，并观察到更高的小鼠小肠体内生物分布，其中它们在α4β7+细胞中积累。我们的LCNP显示了共同提供抗逆转录病毒药物和单克隆抗体以根除艾滋病毒宿主的潜力。我们开发了包含α4β7单克隆抗体（mAb）的核-壳纳米颗粒，用于选择性地将治疗剂递送至肠道相关淋巴组织（GALT）中的肠道归巢T细胞，同时阻断HIV感染。我们证明了蛋白酶抑制剂和α4β7 mAb组合的体外抗逆转录病毒活性增强，并在恒河猴原代细胞和小鼠中显示出靶向功能。这些数据表明，我们的LCNP递送系统具有将ARV药物和mAb共同递送到解剖学和细胞HIV储库的潜力，以减小储库大小并潜在地根除病毒。
A major sanctuary site for HIV infection is the gut-associated lymphoid tissue (GALT). The α4β7 integrin gut homing receptor is a promising therapeutic target for the virus reservoir because it leads to migration of infected cells to the GALT and facilitates HIV infection. Here, we developed a core-shell nanoparticle incorporating the α4β7 monoclonal antibody (mAb) as a dual-functional ligand for selectively targeting a protease inhibitor (PI) to gut-homing T cells in the GALT while simultaneously blocking HIV infection. Our nanoparticles significantly reduced cytotoxicity of the PI and enhanced its in vitro antiviral activity in combination with α4β7 mAb. We demonstrate targeting function of our nanocarriers in a human T cell line and primary cells isolated from macaque ileum, and observed higher in vivo biodistribution to the murine small intestines where they accumulate in α4β7+ cells. Our LCNP shows the potential to co-deliver ARVs and mAbs for eradicating HIV reservoirs. We developed core-shell nanoparticles incorporating the α4β7 monoclonal antibody (mAb) for selectively delivering therapeutic agents to gut-homing T cells in the gut-associated lymphoid tissue (GALT), while simultaneously blocking HIV infection. We demonstrate enhanced antiretroviral activity of a protease inhibitor and α4β7 mAb combination in vitro, and show targeting function in rhesus macaque primary cells and in mice. These data demonstrate that our LCNP delivery system has the potential to co-deliver ARV drugs and mAbs to anatomical and cellular HIV reservoirs for the purpose of reducing reservoir size and potentially eradicating the virus.
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影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
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影响因子：
5.8
作者：
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DOI：
10.1073/pnas.0911796106
发表时间：
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影响因子：
11.1
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通讯作者：
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DOI：
10.1073/pnas.1318249111
发表时间：
2014-02-11
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
Dandekar, S