Enhancement of airway gene transfer by DNA nanoparticles using a pH-responsive block copolymer of polyethylene glycol and poly-L-lysine
| Autor: | Pichet Adstamongkonkul, Jung Soo Suk, Anthony J. Kim, Nicholas J. Boylan, Justin Hanes, Samuel K. Lai, Mark J. Cooper, Brian W. Simons |
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| Rok vydání: | 2011 |
| Předmět: |
Materials science
Polymers Biophysics Bioengineering Polyethylene glycol Respiratory Mucosa Gene delivery Article Cell Line Polyethylene Glycols Biomaterials chemistry.chemical_compound Mice PEG ratio Materials Testing Animals Humans Polylysine Drug Carriers Mice Inbred BALB C Molecular Structure Gene Transfer Techniques Epithelial Cells DNA Genetic Therapy Hydrogen-Ion Concentration In vitro chemistry Biochemistry Mechanics of Materials Ceramics and Composites Nanoparticles Female Drug carrier Nucleolin |
| Zdroj: | Biomaterials. 33(7) |
| ISSN: | 1878-5905 |
| Popis: | Highly compacted DNA nanoparticles, composed of single molecules of plasmid DNA compacted with block copolymers of polyethylene glycol and poly-L-lysine (PEG-CK(30)), 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-CH(12)K(18). Inclusion of poly-L-histidine increased the buffering capacity of PEG-CH(12)K(18) to levels comparable with branched polyethyleneimine. PEG-CH(12)K(18) compacted DNA into rod-shaped DNA nanoparticles with similar morphology and colloidal stability as PEG-CK(30) DNA nanoparticles. PEG-CH(12)K(18) 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-CH(12)K(18) DNA nanoparticles improved the in vitro gene transfer by ~20-fold over PEG-CK(30) 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. |
| Databáze: | OpenAIRE |
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