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Enhancement of airway gene transfer by DNA nanoparticles using a pH-responsive block copolymer of polyethylene glycol and poly-l-lysine

Paper ID Volume ID Publish Year Pages File Format Full-Text
7477 553 2012 11 PDF Available
Title
Enhancement of airway gene transfer by DNA nanoparticles using a pH-responsive block copolymer of polyethylene glycol and poly-l-lysine
Abstract

Highly compacted DNA nanoparticles, composed of single molecules of plasmid DNA compacted with block copolymers of polyethylene glycol and poly-l-lysine (PEG-CK30), have shown considerable promise in human gene therapy clinical trials in the nares, but may be less capable of transfecting cells that lack surface nucleolin. To address this potential shortcoming, we formulated pH-responsive DNA nanoparticles that mediate gene transfer via a nucleolin-independent pathway. Poly-l-histidine was inserted between PEG and poly-l-lysine to form a triblock copolymer system, PEG-CH12K18. Inclusion of poly-l-histidine increased the buffering capacity of PEG-CH12K18 to levels comparable with branched polyethyleneimine. PEG-CH12K18 compacted DNA into rod-shaped DNA nanoparticles with similar morphology and colloidal stability as PEG-CK30 DNA nanoparticles. PEG-CH12K18 DNA nanoparticles entered human bronchial epithelial cells (BEAS-2B) that lack surface nucleolin by a clathrin-dependent endocytic mechanism followed by endo-lysosomal processing. Despite trafficking through the degradative endo-lysosomal pathway, PEG-CH12K18 DNA nanoparticles improved the in vitro gene transfer by ∼20-fold over PEG-CK30 DNA nanoparticles, and in vivo gene transfer to lung airways in BALB/c mice by ∼ 3-fold, while maintaining a favorable toxicity profile. These results represent an important step toward the rational development of an efficient gene delivery platform for the lungs based on highly compacted DNA nanoparticles.

Keywords
Cystic fibrosis; Gene therapy; Non-viral; pH buffering
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Enhancement of airway gene transfer by DNA nanoparticles using a pH-responsive block copolymer of polyethylene glycol and poly-l-lysine
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 33, Issue 7, March 2012, Pages 2361–2371
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us