Markedly enhanced skeletal muscle transfection achieved by the ultrasound-targeted delivery of non-viral gene nanocarriers with microbubbles

Caitlin W. Burke, Jung Soo Suk, Anthony J. Kim, Yu Han J. Hsiang, Alexander L. Klibanov, Justin Hanes, Richard J. Price

Research output: Contribution to journalArticle

Abstract

Our goal was to enhance ultrasound (US)-targeted skeletal muscle transfection through the use of poly(ethyleneglycol) (PEG)/polyethylenimine (PEI) nanocomplex gene carriers and adjustments to US and microbubble (MB) parameters. C57BL/6 mice received an intravenous infusion of MBs and either naked luciferase plasmid or luciferase plasmid condensed in PEG/PEI nanocomplexes. Pulsed ultrasound (1 MHz; 0.6 MPa or 0.8 MPa) was applied to the right hindlimb for 12 min. Luciferase activity in both hindlimbs was assessed at 3, 5, 7, and 10 days post-treatment by bioluminescent imaging. When targeted to hindlimb using unsorted MBs and 0.6 MPa US, 7 days after treatment, we observed a > 60-fold increase in luciferase activity in PEG/PEI nanocomplex-treated muscles over muscles treated with naked plasmid DNA. Luciferase activity was consistently greater after treatment with PEG/PEI nanocomplexes at 0.6 MPa as compared to 0.8 MPa. The combination of small diameter MBs and 0.6 MPa US also resulted in significantly greater gene expression when compared to concentration matched intramuscular injections, a control condition in which considerably more PEG/PEI nanocomplexes were present in tissue. This result suggests that, in addition to facilitating PEG/PEI nanocomplex delivery from the bloodstream to tissue, US enhances transfection via one or more secondary mechanisms, including increased cellular uptake and/or trafficking to the nucleus of PEG/PEI nanocomplexes. We conclude that PEG/PEI nanocomplexes may be used to markedly enhance the amplitude of US-MB-targeted skeletal muscle transfection and that activating small MBs with a moderate level (0.6 MPa) of acoustic pressure can further enhance these effects.

Original languageEnglish (US)
Pages (from-to)414-421
Number of pages8
JournalJournal of Controlled Release
Volume162
Issue number2
DOIs
StatePublished - Sep 10 2012

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Keywords

  • Microbubbles
  • Nanomedicine
  • Non-viral gene delivery
  • Polyethylenimine
  • Skeletal muscle
  • Ultrasound

ASJC Scopus subject areas

  • Pharmaceutical Science

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