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One-Pot Parallel Synthesis of Lipid Library via Thiolactone Ring Opening and Screening for Gene Delivery
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2018-03-20 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00007
Mijanur R. Molla 1 , Alexander Böser 1 , Akshita Rana 1 , Karina Schwarz 1 , Pavel A. Levkin 1
Affiliation  

Efficient delivery of nucleic acids into cells is of great interest in the field of cell biology and gene therapy. Despite a lot of research, transfection efficiency and structural diversity of gene-delivery vectors are still limited. A better understanding of the structure–function relationship of gene delivery vectors is also essential for the design of novel and intelligent delivery vectors, efficient in “difficult-to-transfect” cells and in vivo clinical applications. Most of the existing strategies for the synthesis of gene-delivery vectors require multiple steps and lengthy procedures. Here, we demonstrate a facile, three-component one-pot synthesis of a combinatorial library of 288 structurally diverse lipid-like molecules termed “lipidoids” via a thiolactone ring opening reaction. This strategy introduces the possibility to synthesize lipidoids with hydrophobic tails containing both unsaturated bonds and reducible disulfide groups. The whole synthesis and purification are convenient, extremely fast, and can be accomplished within a few hours. Screening of the produced lipidoids using HEK293T cells without addition of helper lipids resulted in identification of highly stable liposomes demonstrating ∼95% transfection efficiency with low toxicity.

中文翻译:

通过硫代内酯开环一键并行合成脂质文库和基因传递筛选

在细胞生物学和基因治疗领域中,将核酸有效地递送到细胞中是非常重要的。尽管进行了大量研究,但是基因递送载体的转染效率和结构多样性仍然受到限制。更好地了解基因传递载体的结构-功能关系对于设计新颖,智能的传递载体也很重要,这种载体在“难转染”细胞和体内临床应用中均有效。现有的大多数合成基因递送载体的策略都需要多个步骤和冗长的过程。在这里,我们展示了一个简单的三组分单锅通过硫代内酯开环反应合成288个结构不同的类脂分子(称为“类脂质”)的组合文库。该策略引入了合成具有疏水性尾巴的类脂质的可能性,所述疏水性尾巴既包含不饱和键又包含可还原的二硫键。整个合成和纯化方便,极快,并且可以在几个小时内完成。在不添加辅助脂质的情况下,使用HEK293T细胞筛选产生的类脂质,可鉴定出高度稳定的脂质体,显示出约95%的转染效率,且毒性低。
更新日期:2018-03-20
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