Pharmaceutical Research

, Volume 30, Issue 2, pp 342–351

Effect of PEGylation on Biodistribution and Gene Silencing of siRNA/Lipid Nanoparticle Complexes

Authors

  • Yanjie Bao
    • Biomedical Engineering and Technology Institute Institutes for Advanced Interdisciplinary ResearchEast China Normal University
    • Nitto Denko Technical Corporation
  • Yi Jin
    • Nitto Denko Technical Corporation
  • Padmanabh Chivukula
    • Nitto Denko Technical Corporation
  • Jun Zhang
    • Nitto Denko Technical Corporation
  • Yun Liu
    • Nitto Denko Technical Corporation
  • Jian Liu
    • Nitto Denko Technical Corporation
  • Jean-Pierre Clamme
    • Nitto Denko Technical Corporation
  • Ram I. Mahato
    • Department of Pharmaceutical SciencesUniversity of Tennessee Health Science Center
  • Dominic Ng
    • Nitto Denko Technical Corporation
  • Wenbin Ying
    • Nitto Denko Technical Corporation
    • Biomedical Engineering and Technology Institute Institutes for Advanced Interdisciplinary ResearchEast China Normal University
    • Biomedical Engineering and Technology Institute Institutes for Advanced Interdisciplinary ResearchEast China Normal University
    • Nitto Denko Technical Corporation
Research Paper

DOI: 10.1007/s11095-012-0874-6

Cite this article as:
Bao, Y., Jin, Y., Chivukula, P. et al. Pharm Res (2013) 30: 342. doi:10.1007/s11095-012-0874-6

ABSTRACT

Purpose

To determine the influence of physicochemical properties of lipid nanoparticles (LNPs) carrying siRNA on their gene silencing in vivo. Mechanistic understanding of how the architecture of the nanoparticle can alter gene expression has also been studied.

Methods

The effect of 3-N-[(ω-methoxypoly(ethylene glycol)2000)carbamoyl]-1,2-dimyristyloxy-propylamine (PEG-C-DMA) on hepatic distribution and FVII gene silencing was determined. FVII mRNA in hepatocytes and liver tissues was determined by Q-PCR. Hepatic distribution was quantified by FACS analysis using Cy5 labeled siRNA.

Results

Gene silencing was highly dependent on the amount of PEG-C-DMA present. FVII gene silencing inversely correlated to the amount of PEG-C-DMA in LNPs. High FVII gene silencing was obtained in vitro and in vivo when the molar ratio of PEG-C-DMA to lipid was 0.5 mol%. Surprisingly, PEGylation didn’t alter the hepatic distribution of the LNPs at 5 h post administration. Instead the amount of PEG present in the LNPs has an effect on red blood cell disruption at low pH.

Conclusion

Low but sufficient PEG-C-DMA amount in LNPs plays an important role for efficient FVII gene silencing in vivo. PEGylation did not alter the hepatic distribution of LNPs, but altered gene silencing efficacy by potentially reducing endosomal disruption.

KEY WORDS

endosomal disruptionFVIIgene silencinghepatic distributionLNPPEG-C-DMA

Copyright information

© Springer Science+Business Media, LLC 2012