Insight into Mechanisms of Cellular Uptake of Lipid Nanoparticles and Intracellular Release of Small RNAs

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• 作者：Bo Yu (1) (2)
  Xinmei Wang (2)
  Chenguang Zhou (2) (3)
  Lesheng Teng (3) (4)
  Wei Ren (5)
  Zhaogang Yang (3)
  Chih-Hsin Shih (6)
  Tianyou Wang (7)
  Robert J. Lee (10) (2) (3) (4)
  Suoqin Tang (8)
  L. James Lee (1) (2) (9)
  
• 关键词：intracellular trafficking ; lipid nanoparticles ; miRNA ; molecular beacon ; siRNA
• 刊名：Pharmaceutical Research
• 出版年：2014
• 出版时间：October 2014
• 年：2014
• 卷：31
• 期：10
• 页码：2685-2695
• 全文大小：2,894 KB
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• 作者单位：Bo Yu (1) (2)
  Xinmei Wang (2)
  Chenguang Zhou (2) (3)
  Lesheng Teng (3) (4)
  Wei Ren (5)
  Zhaogang Yang (3)
  Chih-Hsin Shih (6)
  Tianyou Wang (7)
  Robert J. Lee (10) (2) (3) (4)
  Suoqin Tang (8)
  L. James Lee (1) (2) (9)
  
  1. Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio, USA
  2. NSF Nanoscale Science and Engineering Center (NSEC), The Ohio State University, Columbus, Ohio, USA
  3. Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA
  4. College of Life Sciences, Jinlin University, Changchun, People鈥檚 Republic China
  5. Department of Physiology, The Ohio State University, Columbus, Ohio, USA
  6. Department of Chemical Engineering, Feng Chia University, Taichung, Taiwan
  7. Department of Hematology, Capital Institute of Pediatrics Affiliated Children鈥檚 Hospital, Beijing, People鈥檚 Republic
  10. 500 W. 12th Ave., Columbus, Ohio, 43210, USA
  8. Department of Pediatrics, PLA General Hospital, 20 Fuxing Road, Beijing, 100036, People鈥檚 Republic China
  9. The Ohio State University, 1012 Smith Lab, 174 West 18th Ave., Columbus, Ohio, 43210, USA
  
• ISSN：1573-904X

文摘

Purpose Understanding mechanisms of cellular uptake and intracellular release would enable better design of nanocarriers for delivery of nucleic acids such as siRNA and microRNA (miRNA). Method In this study, we investigated cellular pharmacokinetics of siRNA by co-encapsulating fluorescently labeled siRNA and molecular beacon (MB) in four different formulations of cationic lipid nanoparticles (LNPs). A miRNA mimic was also used as a probe for investigating cellular pharmacokinetics, which correlated well with RNAi activities. Results We tried to find the best LNP formulation based on the combination of DOTMA and DODMA. When the DOTMA/DODMA ratio was at 5/40, the LNP containing a luciferase siRNA produced the highest gene silencing activity. The superior potency of DOTMA/DODMA could be attributed to higher uptake and improved ability to facilitate siRNA release from endosomes subsequent to uptake. Conclusions Our findings may provide new insights into RNAi transfection pathways and have implications on cationic LNP design.