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Combinatorial Synthesis of a Lipidoid Library by Thiolactone Chemistry: In Vitro Screening and In Vivo Validation for siRNA Delivery.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-02-28 , DOI: 10.1021/acs.bioconjchem.0c00013 Mijanur R Molla 1, 2 , Shraddha Chakraborty 1 , Leonel Munoz Sagredo 1, 3 , Markus Drechsler 4 , Véronique Orian Rousseau 1 , Pavel A Levkin 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-02-28 , DOI: 10.1021/acs.bioconjchem.0c00013 Mijanur R Molla 1, 2 , Shraddha Chakraborty 1 , Leonel Munoz Sagredo 1, 3 , Markus Drechsler 4 , Véronique Orian Rousseau 1 , Pavel A Levkin 1
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Transcriptional inhibition by small interfering RNA (siRNA) delivery using synthetic transfection agents eliminates the subsequent risk of introducing mutations in relevant genes, as opposed to viral vectors. However, synthetic vectors with comparable transfection efficiency to that of viral vectors are yet to be developed. Hence, synthesizing new transfection vehicles with low toxicity is important. In this study, a library of lipid-like molecules (lipidoids) was synthesized by thiolactone chemistry. This library facilitated nonviral delivery of siRNA to mammalian cells, inducing sequence-specific knockdown of a target gene. The liposomal nanoparticles complexed with anti-green fluorescent protein (GFP) siRNA were successfully screened for transfection efficiency using a HeLa-GFP cell line. The five best-performing lipidoids identified in the screening were found to exhibit superior GFP-knockdown efficiency compared with commercially available transfection reagents. The efficiency of siRNA delivery by one of these lipidoids with minimal toxicity was further successfully evaluated in vivo using Kdrl:EGFP zebrafish embryos as a model system. Our study would be important as a facile synthetic route of efficient nonviral nucleic acid delivery to live cells and organisms.
中文翻译：
通过硫内酯化学的类脂库的组合合成：siRNA递送的体外筛选和体内验证。
与病毒载体相反，使用合成转染剂通过小干扰RNA（siRNA）传递进行转录抑制可消除随后在相关基因中引入突变的风险。然而，尚未开发出具有与病毒载体相当的转染效率的合成载体。因此，合成具有低毒性的新的转染载体是重要的。在这项研究中，通过硫代内酯化学合成了类脂质分子（类脂）库。该文库促进了siRNA向哺乳动物细胞的非病毒传递，从而诱导了靶基因的序列特异性敲低。使用HeLa-GFP细胞系成功地筛选了与抗绿色荧光蛋白（GFP）siRNA复合的脂质体纳米颗粒的转染效率。与市场上可买到的转染试剂相比，在筛选中鉴定出的五个表现最佳的类脂质表现出优异的GFP击倒效率。使用Kdrl：EGFP斑马鱼胚胎作为模型系统，进一步成功地评估了其中一种脂质体的siRNA传递效率最低的效率。我们的研究作为有效地将非病毒核酸有效递送至活细胞和生物体的简便合成途径将非常重要。
更新日期：2020-03-02
中文翻译：
通过硫内酯化学的类脂库的组合合成：siRNA递送的体外筛选和体内验证。
与病毒载体相反，使用合成转染剂通过小干扰RNA（siRNA）传递进行转录抑制可消除随后在相关基因中引入突变的风险。然而，尚未开发出具有与病毒载体相当的转染效率的合成载体。因此，合成具有低毒性的新的转染载体是重要的。在这项研究中，通过硫代内酯化学合成了类脂质分子（类脂）库。该文库促进了siRNA向哺乳动物细胞的非病毒传递，从而诱导了靶基因的序列特异性敲低。使用HeLa-GFP细胞系成功地筛选了与抗绿色荧光蛋白（GFP）siRNA复合的脂质体纳米颗粒的转染效率。与市场上可买到的转染试剂相比，在筛选中鉴定出的五个表现最佳的类脂质表现出优异的GFP击倒效率。使用Kdrl：EGFP斑马鱼胚胎作为模型系统，进一步成功地评估了其中一种脂质体的siRNA传递效率最低的效率。我们的研究作为有效地将非病毒核酸有效递送至活细胞和生物体的简便合成途径将非常重要。
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