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T14diLys/DOPE脂质体：基于小干扰RNA的基因敲低的创新选择？

T14diLys/DOPE Liposomes: An Innovative Option for siRNA-Based Gene Knockdown?

作者信息

Meinhard Sophie, Erdmann Frank, Lucas Henrike, Krabbes Maria, Krüger Stephanie, Wölk Christian, Mäder Karsten

机构信息

Department of Pharmaceutical Technology, Faculty of Natural Sciences I, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany.

Department of Pharmaceutical Pharmacology and Toxicology, Faculty of Natural Sciences I, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120 Halle/Saale, Germany.

出版信息

Pharmaceutics. 2024 Dec 27;17(1):25. doi: 10.3390/pharmaceutics17010025.

DOI:10.3390/pharmaceutics17010025
PMID:39861674
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11769127/
Abstract

BACKGROUND/OBJECTIVES: Bringing small interfering RNA (siRNA) into the cell cytosol to achieve specific gene silencing is an attractive but also very challenging option for improved therapies. The first step for successful siRNA delivery is the complexation with a permanent cationic or ionizable compound. This protects the negatively charged siRNA and enables transfection through the cell membrane. The current study explores the performance of the innovative, ionizable lipid 2-Tetradecylhexadecanoic acid-(2-bis{[2-(2,6-diamino-1-oxohexyl)amino]ethyl}aminoethyl)-amide (T14diLys), in combination with 1,2-dioleoyl--glycero-3-phosphoethanolamine (DOPE), for siRNA delivery and the impact of the production method (sonication vs. extrusion) on the particle properties.

METHODS

Liposomes were produced either with sonication or extrusion and characterized. The extruded liposomes were combined with siRNA at different N/P ratios and investigated in terms of size zeta potential, encapsulation efficiency, lipoplex stability against RNase A, and knockdown efficiency using enhanced green fluorescent protein (eGFP)-marked colon adenocarcinoma cells.

RESULTS

The liposomes prepared by extrusion were smaller and had a narrower size distribution than the sonicated ones. The combination of siRNA and liposomes at a nitrogen-to-phosphate (N/P) ratio of 5 had optimal particle properties, high encapsulation efficiency, and lipoplex stability. Gene knockdown tests confirmed this assumption.

CONCLUSIONS

Liposomes produced with extrusion were more reproducible and provided enhanced particle properties. The physicochemical characterization and in vitro experiments showed that an N/P ratio of 5 was the most promising ratio for siRNA delivery.

摘要

背景/目的：将小干扰RNA（siRNA）导入细胞溶质以实现特定基因沉默，对于改进治疗方法来说是一个有吸引力但极具挑战性的选择。成功递送siRNA的第一步是与永久性阳离子或可电离化合物形成复合物。这可以保护带负电荷的siRNA，并使其能够通过细胞膜进行转染。本研究探讨了创新的可电离脂质2-十四烷基十六烷酸-（2-双{[2-（2,6-二氨基-1-氧代己基）氨基]乙基}氨基乙基）-酰胺（T14diLys）与1,2-二油酰基-sn-甘油-3-磷酸乙醇胺（DOPE）联合用于siRNA递送的性能，以及生产方法（超声处理与挤压）对颗粒性质的影响。

方法

通过超声处理或挤压制备脂质体并进行表征。将挤压后的脂质体与不同N/P比的siRNA混合，并从粒径、zeta电位、包封率、脂质体对核糖核酸酶A的稳定性以及使用增强型绿色荧光蛋白（eGFP）标记的结肠腺癌细胞的敲低效率等方面进行研究。

结果

通过挤压制备的脂质体比超声处理的脂质体更小，粒径分布更窄。siRNA与脂质体在氮磷比（N/P）为5时组合具有最佳的颗粒性质、高包封率和脂质体稳定性。基因敲低试验证实了这一假设。

结论

通过挤压制备的脂质体更具可重复性，并具有更好的颗粒性质。物理化学表征和体外实验表明，N/P比为5是siRNA递送最有前景的比例。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/76c5aeb4669c/pharmaceutics-17-00025-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/cb542f4463e7/pharmaceutics-17-00025-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/a4bc01f9d0d0/pharmaceutics-17-00025-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/462fa9edf190/pharmaceutics-17-00025-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/55349dc7ac65/pharmaceutics-17-00025-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/595ec218176c/pharmaceutics-17-00025-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/572967db28b4/pharmaceutics-17-00025-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/0e165bb5a89b/pharmaceutics-17-00025-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/50f770c5fa70/pharmaceutics-17-00025-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/f06b3009a520/pharmaceutics-17-00025-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/76c5aeb4669c/pharmaceutics-17-00025-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/cb542f4463e7/pharmaceutics-17-00025-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/a4bc01f9d0d0/pharmaceutics-17-00025-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/462fa9edf190/pharmaceutics-17-00025-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/55349dc7ac65/pharmaceutics-17-00025-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/595ec218176c/pharmaceutics-17-00025-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/572967db28b4/pharmaceutics-17-00025-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/0e165bb5a89b/pharmaceutics-17-00025-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/50f770c5fa70/pharmaceutics-17-00025-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/f06b3009a520/pharmaceutics-17-00025-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e47/11769127/76c5aeb4669c/pharmaceutics-17-00025-g010.jpg

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