Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design.
Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design.
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DOI：
10.1016/j.omtn.2018.02.003
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Sijts AJAM
中科院分区：
文献类型：
--
作者：
de Groot AM;Thanki K;Gangloff M;Falkenberg E;Zeng X;van Bijnen DCJ;van Eden W;Franzyk H;Nielsen HM;Broere F;Gay NJ;Foged C;Sijts AJAM
基于小干扰RNA(SiRNA)的治疗药物在抗病毒和抗炎方面具有潜在的应用前景。为了将siRNA通过细胞膜传递到靶细胞胞浆中的RNAi途径，探索了非病毒纳米颗粒传递方法。最近，我们发现，与以二油酰基三甲基丙烷(DOTAP)修饰的脂质-聚合物杂化纳米粒(LPN)为脂质成分相比，将siRNA包裹在基于聚(DL-乳酸-乙醇酸共聚)(PLGA)和阳离子类脂材料(类脂)的脂质-聚合物杂化纳米粒(LPN)中，显著提高了siRNA在细胞内的转运。然而，这些阳离子脂类的潜在免疫调节作用仍未被探索。通过在体外测试类脂和DOTAP的天然免疫受体激活特性，我们发现类脂和DOTAP都不能激活人Toll样受体(TLR)2、3、7和9。然而，与DOTAP相反，类脂是TLR4的强烈激动剂，在体外激活小鼠的抗原提呈细胞。利用基于晶体结构的预测模型，在硅胶中进一步证实了这种激动剂的作用。此外，作为siRNA传递的参考配方，以脂复合物或稳定的核酸脂质颗粒形式的类脂被证明激活了TLR4。然而，通过将类脂和PLGA结合到LPN中，TLR4的激活被取消。因此，脂类介导的TLR4在siRNA递送过程中的激活可以通过优化配方设计来调节。
Therapeutics based on small interfering RNA (siRNA) have promising potential as antiviral and anti-inflammatory agents. To deliver siRNA across cell membranes to reach the RNAi pathway in the cytosol of target cells, non-viral nanoparticulate delivery approaches are explored. Recently, we showed that encapsulation of siRNA in lipid-polymer hybrid nanoparticles (LPNs), based on poly(DL-lactic-co-glycolic acid) (PLGA) and cationic lipid-like materials (lipidoids), remarkably enhances intracellular delivery of siRNA as compared to siRNA delivery with LPNs modified with dioleoyltrimethylammoniumpropane (DOTAP) as the lipid component. However, the potential immune modulation by these cationic lipids remains unexplored. By testing lipidoids and DOTAP for innate immune-receptor-activating properties in vitro, we found that neither lipidoids nor DOTAP activate human Toll-like receptor (TLR) 2, 3, 7, and 9. However, in contrast to DOTAP, lipidoids are strong agonists for TLR4 and activate murine antigen-presenting cells in vitro. This agonistic effect was further confirmed in silico using a prediction model based on crystal structures. Also, lipidoids formulated as lipoplexes or as stable nucleic acid lipid particles, which was the reference formulation for siRNA delivery, proved to activate TLR4. However, by combining lipidoids with PLGA into LPNs, TLR4 activation was abrogated. Thus, lipidoid-mediated TLR4 activation during siRNA delivery may be modulated via optimization of the formulation design.
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影响因子：
3.7
作者：
Irvine, Katherine L.;Gangloff, Monique;Bryant, Clare E.
通讯作者：
Bryant, Clare E.
影响因子：
12.4
作者：
Akinc, Akin;Goldberg, Michael;Anderson, Daniel G.
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Anderson, Daniel G.
影响因子：
14
作者：
Kedmi, Ranit;Ben-Arie, Noa;Peer, Dan
通讯作者：
Peer, Dan
影响因子：
2.1
作者：
GASTEIGER, J;MARSILI, M
通讯作者：
MARSILI, M
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.