Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier

JOURNAL OF CONTROLLED RELEASE

卷:178

Article

Suk, Jung Soo^1,2,3  Kim, Anthony J.¹  Trehan, Kanika^1,5  Schneider, Craig S.^1,4  Cebotaru, Liudmila^1,2  Woodward, Owen M.⁶  Boylan, Nicholas J.⁴  Boyle, Michael P.⁷  Lai, Samuel K.^1,4  Guggino, William B.^1,6  Hanes, Justin^1,2,3,4 

[1] Johns Hopkins Univ, Sch Med, Ctr Nanomed, Baltimore, MD 21231 USA

[2] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA

[5] Johns Hopkins Univ, Dept Mol & Cellular Biol, Baltimore, MD 21218 USA

[6] Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Johns Hopkins Adult Cyst Fibrosis Program, Div Pulm & Crit Care Med, Baltimore, MD 21205 USA

关键词: Airway gene therapy;    Mucus barrier;    DNA nanoparticle;    Multiple particle tracking;   

DOI  :  10.1016/j.jconrel.2014.01.007

来源: Elsevier

【 摘 要 】

Inhaled gene carriers must penetrate the highly viscoelastic and adhesive mucus barrier in the airway in order to overcome rapid mucociliary clearance and reach the underlying epithelium; however, even the most widely used viral gene carriers are unable to efficiently do so. We developed two polymeric gene carriers that compact plasmid DNA into small and highly stable nanoparticles with dense polyethylene glycol (PEG) surface coatings. These highly compacted, densely PEG-coated DNA nanoparticles rapidly penetrate human cystic fibrosis (CF) mucus ex vivo and mouse airway mucus ex situ. Intranasal administration of the mucus penetrating DNA nanoparticles greatly enhanced particle distribution, retention and gene transfer in the mouse lung airways compared to conventional gene carriers. Successful delivery of a full-length plasmid encoding the cystic fibrosis transmembrane conductance regulator protein was achieved in the mouse lungs and airway cells, including a primary culture of mucus-covered human airway epithelium grown at air-liquid interface, without causing acute inflammation or toxicity. Highly compacted mucus penetrating DNA nanoparticles hold promise for lung gene therapy. (C) 2014 Elsevier B.V. All rights reserved.

【 授权许可】

Free