Lipidation of polyethylenimine-based polyplex increases serum stability of bioengineered RNAi agents and offers more consistent tumoral gene knockdown in vivo

Qian Yu Zhang, Pui Yan Ho, Mei Juan Tu, Joseph L. Jilek, Qiu Xia Chen, Su Zeng, Aiming Yu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Recently we have established a novel approach to produce bioengineered noncoding RNA agents (BERAs) in living cells that carry target RNAi molecules (e.g., siRNA and miRNA) and thus act as “prodrugs”. Using GFP-siRNA-loaded BERA (BERA/GFP-siRNA) as a model molecule, this study was to define the in vitro and in vivo knockdown efficiency of BERAs delivered by liposome-polyethylenimine nanocomplex (lipopolyplex or LPP). Compared to in vivo-jetPEI® (IVJ-PEI) and polyplex formulations, LPP offered greater protection of BERA/GFP-siRNA against degradation by serum RNases. Particle sizes and zeta potentials of LPP nanocomplex remained stable over 28 days when stored at 4 °C. Furthermore, comparable levels of BERA/GFP-siRNA were delivered by LPP and IVJ-PEI to luciferase/GFP-expressing human SK-Hep1-Luc-GFP or A549-Luc-GFP cells, which were selectively processed into target GFP-siRNA and subsequently knocked down GFP mRNA and protein levels. In addition, LPP-carried BERA/GFP-siRNA was successfully delivered into xenograft tumors and offered more consistent knockdown of tumoral GFP mRNA level in an orthotopic hepatocellular carcinoma (HCC) SK-Hep1-Luc-GFP xenograft mouse model, while IVJ-PEI formulation showed larger variation. These findings demonstrated that lipidation of polyplexes improved serum stability of biologic RNAi molecules, which was efficiently delivered to orthotopic HCC tissues to knock down target gene expression.

Original languageEnglish (US)
Pages (from-to)537-544
Number of pages8
JournalInternational Journal of Pharmaceutics
Volume547
Issue number1-2
DOIs
StatePublished - Aug 25 2018

Keywords

  • Bioengineering
  • Cancer
  • Lipopolyplex
  • Mouse model
  • Orthotopic HCC
  • RNA delivery
  • siRNA

ASJC Scopus subject areas

  • Pharmaceutical Science

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