کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2500845 1557311 2016 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure, activity and uptake mechanism of siRNA-lipid nanoparticles with an asymmetric ionizable lipid
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی علوم دارویی
پیش نمایش صفحه اول مقاله
Structure, activity and uptake mechanism of siRNA-lipid nanoparticles with an asymmetric ionizable lipid
چکیده انگلیسی

Lipid nanoparticles (LNPs) represent the most advanced platform for the systemic delivery of siRNA. We have previously reported the discovery of novel ionizable lipids with asymmetric lipid tails, enabling potent gene-silencing activity in hepatocytes in vivo; however, the structure and delivery mechanism had not been elucidated. Here, we report the structure, activity and uptake mechanism of LNPs with an asymmetric ionizable lipid. Zeta potential and hemolytic activity of LNPs showed that LNPs were neutral at the pH of the blood compartment but become increasingly charged and fusogenic in the acidic endosomal compartment. 31P NMR experiments indicated that the siRNA was less mobile inside particles, presumably because of an electrostatic interaction with an ionizable lipid. The role of Apolipoprotein E (apoE) was studied using recombinant human apoE both in vitro and in vivo. A comparative study in wild-type and apoE-deficient mice revealed that apoE significantly influenced the in vivo biodistribution of LNPs and enhanced the cellular uptake. Pretreatment of mice with siRNA targeting low-density lipoprotein receptor (LDLR) impaired gene-silencing of the following siRNA treatment, demonstrating that in vivo activity of LNPs is dependent on LDLR. Our studies on the detailed mechanism should lead to the creation of more sophisticated LNP-based RNAi therapeutics.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: International Journal of Pharmaceutics - Volume 510, Issue 1, 20 August 2016, Pages 350–358
نویسندگان
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