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Fluorinated Oligoethylenimine Nanoassemblies for Efficient siRNA-Mediated Gene Silencing in Serum-Containing Media by Effective Endosomal Escape
Nano Letters ( IF 9.6 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acs.nanolett.8b02553 Tingbin Zhang 1, 2 , Yuanyu Huang 3 , Xiaowei Ma 2 , Ningqiang Gong 2 , Xiaoli Liu 2 , Lu Liu 2, 4 , Xiaoxia Ye 2 , Bo Hu 3 , Chunhui Li 3 , Jian-Hua Tian 1 , Andrea Magrini 5 , Jinchao Zhang 6 , Weisheng Guo 7 , Jin-Feng Xing 1 , Massimo Bottini 2, 4 , Xing-Jie Liang 2
Nano Letters ( IF 9.6 ) Pub Date : 2018-09-21 00:00:00 , DOI: 10.1021/acs.nanolett.8b02553 Tingbin Zhang 1, 2 , Yuanyu Huang 3 , Xiaowei Ma 2 , Ningqiang Gong 2 , Xiaoli Liu 2 , Lu Liu 2, 4 , Xiaoxia Ye 2 , Bo Hu 3 , Chunhui Li 3 , Jian-Hua Tian 1 , Andrea Magrini 5 , Jinchao Zhang 6 , Weisheng Guo 7 , Jin-Feng Xing 1 , Massimo Bottini 2, 4 , Xing-Jie Liang 2
Affiliation
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Efficient small interfering RNA (siRNA) delivery in the presence of serum is of crucial importance for effective gene therapy. Fluorinated vectors are considered to be attractive candidates for siRNA-mediated gene therapy because of their delivery efficacy in serum-containing media. However, the mechanisms driving the superior gene transfection behavior of fluorinated vectors are still not well-understood, and comprehensive investigations are warranted. Herein, we fabricated a library of perfluorooctanoyl fluoride-fluorinated (PFF-fluorinated) oligoethylenimines (fxOEIs, x is the PFF:OEI feeding ratio), which can readily form nanoassemblies (fxOEI NAs) capable of efficient siRNA delivery in cells cultured in medium both devoid of and supplemented with fetal bovine serum (FBS). The gene silencing test in serum-containing medium revealed that the f0.7OEI/siRNA NAs achieved a luciferase silencing of ∼88.4% in Luc-HeLa cells cultured in FBS-containing medium, which was almost 2-fold greater than the silencing efficacy of siRNA delivered by the commercially available vector Lipo 2000 (∼48.8%). High levels of apolipoprotein B silencing were also achieved by f0.7OEI/siRNA NAs in vivo. For an assessment of the underlying mechanisms of the efficacy of gene silencing of fluorinated vectors, two alkylated OEIs, aOEI-C8 and aOEI-C12, were fabricated as controls with similar molecular structure and hydrophobicity to that of f0.7OEI, respectively. In vitro investigations showed that the superior gene delivery exhibited by f0.7OEI NAs derived from the potent endosomal disruption capability of fluorinated vectors in the presence of serum, which was essentially attributed to the serum protein adsorption resistance of the f0.7OEI NAs. Therefore, this work provides an innovative approach to siRNA delivery as well as insights into fluorine-associated serum resistance.
中文翻译：
通过有效的内膜逸出，在含血清培养基中有效地沉默siRNA介导的基因的氟化Oligoethylenimine纳米组件。
在血清存在下有效的小干扰RNA（siRNA）传递对于有效的基因治疗至关重要。氟化载体因其在含血清的培养基中的输送效率而被认为是siRNA介导的基因治疗的诱人候选物。但是，尚不清楚如何驱动氟化载体的优异基因转染行为的机制，因此有必要进行全面的研究。在这里，我们制作了一个全氟辛基氟氟化（PFF氟化）低聚亚乙基亚胺（f x OEI，x是PFF：OEI进料比）的文库，它很容易形成纳米组装（f xOEI NAs）能够在不含和补充胎牛血清（FBS）的培养基中培养的细胞中有效地传递siRNA。在含血清的培养基中进行的基因沉默测试显示，在含FBS的培养基中培养的Luc-HeLa细胞中，f 0.7 OEI / siRNA NAs的荧光素酶沉默达到〜88.4％，几乎是其沉默效率的2倍。由市售载体Lipo 2000递送的siRNA（约48.8％）。体内f 0.7 OEI / siRNA NAs也实现了高水平的载脂蛋白B沉默。为了评估氟化载体基因沉默功效的潜在机制，分别制备了两个烷基化的OEI，aOEI-C8和aOEI-C12作为具有与f 0.7 OEI相似的分子结构和疏水性的对照。体外研究表明，f 0.7 OEI NAs具有优异的基因传递能力，这是由于在存在血清的情况下氟化载体的强大内体破坏能力所致，这基本上归因于f 0.7 OEI NAs的血清蛋白吸附抗性。因此，这项工作为siRNA的传递提供了创新的方法，并提供了对氟相关血清耐药性的见解。
更新日期：2018-09-21
中文翻译：
通过有效的内膜逸出，在含血清培养基中有效地沉默siRNA介导的基因的氟化Oligoethylenimine纳米组件。
在血清存在下有效的小干扰RNA（siRNA）传递对于有效的基因治疗至关重要。氟化载体因其在含血清的培养基中的输送效率而被认为是siRNA介导的基因治疗的诱人候选物。但是，尚不清楚如何驱动氟化载体的优异基因转染行为的机制，因此有必要进行全面的研究。在这里，我们制作了一个全氟辛基氟氟化（PFF氟化）低聚亚乙基亚胺（f x OEI，x是PFF：OEI进料比）的文库，它很容易形成纳米组装（f xOEI NAs）能够在不含和补充胎牛血清（FBS）的培养基中培养的细胞中有效地传递siRNA。在含血清的培养基中进行的基因沉默测试显示，在含FBS的培养基中培养的Luc-HeLa细胞中，f 0.7 OEI / siRNA NAs的荧光素酶沉默达到〜88.4％，几乎是其沉默效率的2倍。由市售载体Lipo 2000递送的siRNA（约48.8％）。体内f 0.7 OEI / siRNA NAs也实现了高水平的载脂蛋白B沉默。为了评估氟化载体基因沉默功效的潜在机制，分别制备了两个烷基化的OEI，aOEI-C8和aOEI-C12作为具有与f 0.7 OEI相似的分子结构和疏水性的对照。体外研究表明，f 0.7 OEI NAs具有优异的基因传递能力，这是由于在存在血清的情况下氟化载体的强大内体破坏能力所致，这基本上归因于f 0.7 OEI NAs的血清蛋白吸附抗性。因此，这项工作为siRNA的传递提供了创新的方法，并提供了对氟相关血清耐药性的见解。
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