Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors

Shashank R. Sirsi, Sonia L. Hernandez, Lukasz Zielinski, Henning Blomback, Adel Koubaa, Milo Synder, Shunichi Homma, Jessica J. Kandel, Darrell J. Yamashiro, Mark A. Borden

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.

Original languageEnglish (US)
Pages (from-to)224-234
Number of pages11
JournalJournal of Controlled Release
Volume157
Issue number2
DOIs
StatePublished - Jan 30 2012

Keywords

  • Gene delivery
  • Polyethylene glycol
  • Polyethylenimine
  • Theranostic
  • Tumor
  • Ultrasound contrast agent

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Sirsi, S. R., Hernandez, S. L., Zielinski, L., Blomback, H., Koubaa, A., Synder, M., Homma, S., Kandel, J. J., Yamashiro, D. J., & Borden, M. A. (2012). Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors. Journal of Controlled Release, 157(2), 224-234. https://doi.org/10.1016/j.jconrel.2011.09.071