275826 Nanomedicines That Overcome Extra- and Intracellular Barriers
No gene delivery system, viral or non-viral, has shown evidence of efficiently penetrating the human mucus barrier; this reality may account in part for the limited success in clinical trials for CF gene therapy to date. Gene vectors that fail to penetrate airway mucus layers are ultimately cleared from the lungs via mucus clearance mechanisms. In addition, poor gene transfer to the airway epithelium has been attributed to a number of cellular barriers, including poor cellular uptake across the apical membrane, unproductive intracellular trafficking, and inefficient nuclear import.
To potentially overcome these formidable barriers, we developed a polymeric nanoparticle platform capable of penetrating sputum expectorated from the lungs of patients with cystic fibrosis (CF), while maintaining an ability to provide efficient airway gene transfer in mice and in human airway epithelial cells grown at air-liquid interface. Mucus penetrating nanoparticles markedly enhanced particle diffusion in CF sputum, leading to enhanced particle distribution, retention and gene transfer in the mouse airways. These results represent an important step toward the rational development of an efficient nanoparticle platform for the lung diseases.
John C. Crocker (University of Pennsylvania)
Daniel A. Hammer (University of Pennsylvania)
Justin Hanes (Johns Hopkins University)
Funding: NIH Fellowship (F32 HL103137)