Lipid-Modified Aminoglycosides for mRNA Delivery to the Liver.
Lipid-Modified Aminoglycosides for mRNA Delivery to the Liver.
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DOI：
10.1002/adhm.201901487
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发表时间：
2020-04
影响因子：
10
通讯作者：
Siegwart DJ
中科院分区：
文献类型：
--
作者：
Yu X;Liu S;Cheng Q;Wei T;Lee S;Zhang D;Siegwart DJ
阳离子脂质纳米颗粒（LNPs）被广泛用作核酸的载体。大多数合成阳离子脂质的途径都来源于简单的胺核。通过从含有碱性氮原子的天然产物开始，可以获得更大的化学多样性，这为更复杂的分子提供了途径。天然构建块尚未得到广泛的探索，例如氨基糖苷类，它们在结构和功能上都对开发新的核酸传递载体很感兴趣。在此，我们探索阳离子脂质修饰氨基糖苷（CLAs）作为信使RNA （mRNA）递送的载体家族。CLAs是由天然存在的氨基糖苷与烷基环氧化物和丙烯酸酯偶联合成的。顶击（GT-EP10）能够以0.05 mg/kg的剂量将Luc mRNA传递给C57BL/6小鼠，在肝脏中达到107的平均发光强度。使用Lox-Stop-Lox TdTomato小鼠模型进一步证明这种高效的mRNA传递系统可能用于基因编辑。成功递送人促红细胞生成素（EPO） mRNA表明，基于cla的LNPs在未来有希望递送治疗性核酸。
Cationic lipid nanoparticles (LNPs) are widely used as carriers for delivery of nucleic acids. Most synthetic routes towards cationic lipids have derived from simple amine cores. Greater chemical diversity could be obtained through starting with natural products containing basic nitrogen atoms, which offers routes to more complex molecules. Natural building blocks have not been extensively explored, such as aminoglycosides which are both structurally and functionally interesting for developing new carriers for nucleic acid delivery. Herein, we explore cationic lipid-modified aminoglycosides (CLAs) as a family of vehicles for messenger RNA (mRNA) delivery. CLAs were synthesized from natural existing aminoglycosides coupling with alkyl epoxides and acrylates. The top hit (GT-EP10) was able to deliver Luc mRNA to C57BL/6 mice at a dose of 0.05 mg/kg to achieve a 107 average luminescence intensity in the liver. The Lox-Stop-Lox TdTomato mouse model was used to further demonstrate that this efficient mRNA delivery system could be potentially used for gene editing. Successful delivery of human erythropoietin (EPO) mRNA shows that CLA-based LNPs have promising opportunities for delivery of therapeutic nucleic acids in the future.
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影响因子：
10.8
作者：
Kauffman, Kevin J.;Dorkin, J. Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
DOI：
10.1038/mtna.2012.28
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--
聚合物 - 含量纳米颗粒，用于将mRNA全身递送到肺部。
DOI：
10.1002/anie.201608450
发表时间：
2016-10-24
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Kaczmarek JC;Patel AK;Kauffman KJ;Fenton OS;Webber MJ;Heartlein MW;DeRosa F;Anderson DG
通讯作者：
Anderson DG
DOI：
10.1016/j.omtn.2017.11.005
发表时间：
2018-03-02
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Kauffman KJ;Oberli MA;Dorkin JR;Hurtado JE;Kaczmarek JC;Bhadani S;Wyckoff J;Langer R;Jaklenec A;Anderson DG
通讯作者：
Anderson DG
影响因子：
10.8
作者：
Kaczmarek JC;Kauffman KJ;Fenton OS;Sadtler K;Patel AK;Heartlein MW;DeRosa F;Anderson DG
通讯作者：
Anderson DG