N-acetylcysteine Enhances Cystic Fibrosis Sputum Penetration and Airway Gene Transfer by Highly Compacted DNA Nanoparticles
| Autor: | Nicholas J. Boylan, Pamela L. Zeitlin, Benjamin C. Tang, Craig S. Schneider, Jung Soo Suk, Mark J. Cooper, Michael P. Boyle, Samuel K. Lai, Kanika Trehan, Justin Hanes, Jung-Ming G. Lin |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cystic Fibrosis Genetic enhancement Respiratory System medicine.disease_cause Cystic fibrosis Polyethylene Glycols Diffusion Acetylcysteine Mice Biopolymers 0302 clinical medicine Transduction Genetic Gene expression Drug Discovery Polylysine Expectorants 0303 health sciences Viscosity 3. Good health 030220 oncology & carcinogenesis Molecular Medicine Female Original Article medicine.symptom Plasmids medicine.drug Adult Biology Young Adult 03 medical and health sciences medicine Genetics Animals Humans Molecular Biology 030304 developmental biology Pharmacology Pseudomonas aeruginosa Mucins Sputum DNA Genetic Therapy medicine.disease Mucus Molecular biology Mice Inbred C57BL Nanoparticles Nasal administration |
| Zdroj: | Molecular Therapy. 19(11):1981-1989 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2011.160 |
| Popis: | For effective airway gene therapy of cystic fibrosis (CF), inhaled gene carriers must first penetrate the hyperviscoelastic sputum covering the epithelium. Whether clinically studied gene carriers can penetrate CF sputum remains unknown. Here, we measured the diffusion of a clinically tested nonviral gene carrier, composed of poly-l-lysine conjugated with a 10 kDa polyethylene glycol segment (CK(30)PEG(10k)). We found that CK(30)PEG(10k)/DNA nanoparticles were trapped in CF sputum. To improve gene carrier diffusion across sputum, we tested adjuvant regimens consisting of N-acetylcysteine (NAC), recombinant human DNase (rhDNase) or NAC together with rhDNase. While rhDNase alone did not enhance gene carrier diffusion, NAC and NAC + rhDNase increased average effective diffusivities by 6-fold and 13-fold, respectively, leading to markedly greater fractions of gene carriers that may penetrate sputum layers. We further tested the adjuvant effects of NAC in the airways of mice with Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced mucus hypersecretion. Intranasal dosing of NAC prior to CK(30)PEG(10k)/DNA nanoparticles enhanced gene expression by up to ~12-fold compared to saline control, reaching levels observed in the lungs of mice without LPS challenge. Our findings suggest that a promising synthetic nanoparticle gene carrier may transfer genes substantially more effectively to lungs of CF patients if administered following adjuvant mucolytic therapy with NAC or NAC + rhDNase. |
| Databáze: | OpenAIRE |
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