Effect of PEGylation on biodistribution and gene silencing of siRNA/lipid nanoparticle complexes

Yanjie Bao, Yi Jin, Padmanabh Chivukula, Jun Zhang, Yun Liu, Jian Liu, Jean Pierre Clamme, Ram I. Mahato, Dominic Ng, Wenbin Ying, Yiting Wang, Lei Yu

Research output: Contribution to journalArticle

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)342-351
Number of pages10
JournalPharmaceutical Research
Volume30
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • FVII
  • LNP
  • PEG-C-DMA
  • endosomal disruption
  • gene silencing
  • hepatic distribution

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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    Bao, Y., Jin, Y., Chivukula, P., Zhang, J., Liu, Y., Liu, J., Clamme, J. P., Mahato, R. I., Ng, D., Ying, W., Wang, Y., & Yu, L. (2013). Effect of PEGylation on biodistribution and gene silencing of siRNA/lipid nanoparticle complexes. Pharmaceutical Research, 30(2), 342-351. https://doi.org/10.1007/s11095-012-0874-6