Influence of nano-carrier architecture on in vitro siRNA delivery performance and in vivo biodistribution: Polyplexes vs micelleplexes

Dana J. Gary, Hoyoung Lee, Rahul Sharma, Jae Sung Lee, Youngwook Kim, Zheng Yun Cui, Di Jia, Valorie D. Bowman, Paul R. Chipman, Lei Wan, Yi Zou, Guangzhao Mao, Keunchil Park, Brittney Shea Herbert, Stephen F. Konieczny, You Yeon Won

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Micelle-based siRNA carriers ("micelleplexes") were prepared from the A-B-C triblock copolymer polyethylene glycol)-poly(n-butyl acrylate)-poly(2-(dimethylamino)ethyl methacrylate) (PEG-PnBA-PDMAEMA), and their in vitro performance and in vivo biodistribution properties were compared with the benchmark PEGylated and basic polycation systems PEG-PDMAEMA and PDMAEMA, respectively. The micelle architecture, incorporating increased PEG shielding and a larger particle size (∼50 nm) than polycation-based complexes (polyplexes; ∼10 nm), enhances siRNA delivery performance in two important aspects: in vitro gene silencing efficiency and in vivo tumor accumulation. The in vitro gene silencing efficiency of the micelleplexes (24% in HeLa cells) was significantly better than the statistically insignificant levels observed for PDMAEMA and PEG-PDMAEMA polyplexes under identical conditions. This enhancement is linked to the different mechanisms by which micelleplexes are internalized (i.e., caveolar, etc.) compared to PDMAEMA and PEG-PDMAEMA polyplexes. Folate-functionalization significantly improved micelleplex uptake but had negligible influence on gene-silencing efficiency, suggesting that this parameter is not limited by cellular internalization. In vivo biodistribution analysis revealed that siRNA delivered by micelleplexes was more effectively accumulated and retained in tumor tissues than that delivered by PEGylated polyplexes. Overall, the micelle particle size and architecture appear to improve in vitro and in vivo delivery characteristics without significantly changing other properties, such as cytotoxicity and resistance to enzymes and dissociation. The self-assembled nature of micelleplexes is expected to enable incorporation of imaging modalities inside the hydrophobic micelle core, thus combining therapeutic and diagnostic capabilities. The findings from the present study suggest that the micelleplex-type carrier architecture is a useful platform for potential theranostic and tumor-targeting applications.

Original languageEnglish (US)
Pages (from-to)3493-3505
Number of pages13
JournalACS Nano
Volume5
Issue number5
DOIs
StatePublished - May 24 2011

Keywords

  • In vitro performance
  • In vivo biodistribution
  • Micelleplex
  • Nanocarrier
  • Polyplex
  • siRNA delivery

ASJC Scopus subject areas

  • Engineering(all)
  • Materials Science(all)
  • Physics and Astronomy(all)

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  • Cite this

    Gary, D. J., Lee, H., Sharma, R., Lee, J. S., Kim, Y., Cui, Z. Y., Jia, D., Bowman, V. D., Chipman, P. R., Wan, L., Zou, Y., Mao, G., Park, K., Herbert, B. S., Konieczny, S. F., & Won, Y. Y. (2011). Influence of nano-carrier architecture on in vitro siRNA delivery performance and in vivo biodistribution: Polyplexes vs micelleplexes. ACS Nano, 5(5), 3493-3505. https://doi.org/10.1021/nn102540y