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

JOURNAL OF CONTROLLED RELEASE

卷:157

Article

Sirsi, Shashank R.¹  Hernandez, Sonia L.²  Zielinski, Lukasz³  Blomback, Henning³  Koubaa, Adel³  Synder, Milo³  Homma, Shunichi⁴  Kandel, Jessica J.⁵  Yamashiro, Darrell J.^2,5  Borden, Mark A.¹ 

[1] Univ Colorado, Dept Mech Engn, Boulder, CO 80309 USA

[2] Columbia Univ, Dept Pediat & Pathol, New York, NY 10032 USA

[3] Columbia Univ, Dept Chem Engn, New York, NY 10027 USA

[4] Columbia Univ, Dept Cardiol, New York, NY 10032 USA

[5] Columbia Univ, Dept Surg, New York, NY 10032 USA

关键词: Theranostic;    Ultrasound contrast agent;    Gene delivery;    Tumor;    Polyethylenimine;    Polyethylene glycol;   

DOI  :  10.1016/j.jconrel.2011.09.071

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier B.V. All rights reserved.

【 授权许可】

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