PEI-engineered respirable particles delivering a decoy oligonucleotide to NF-κB: inhibiting MUC2 expression in LPS-stimulated airway epithelial cells

• Published in: PloS one 2012-10, Vol.7 (10), p.e46457-e46457
• Main Authors: Ungaro, Francesca, De Stefano, Daniela, Giovino, Concetta, Masuccio, Alessia, Miro, Agnese, Sorrentino, Raffaella, Carnuccio, Rosa, Quaglia, Fabiana
• Format: Article
• Language: English
• Subjects: Airway management; Biology; Bronchi - cytology; Bronchi - drug effects; Bronchi - metabolism; Cells, Cultured; Composite materials; Controlled release; Cystic fibrosis; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Gene expression; Humans; Inhibition; Interleukin 8; Interleukin-8 - genetics; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lung diseases; Materials Science; Medicine; Microscopy, Electron, Scanning; Mucin; Mucin-2 - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Oligonucleotides; Oligonucleotides - administration & dosage; Oligonucleotides - chemistry; Particulate composites; Particulates; Pharmaceuticals; Pharmacology; Polyethyleneimine; Polyethyleneimine - chemistry; Polylactide-co-glycolide; Pseudomonas aeruginosa; Respiratory tract; Sustained release; Therapy; Translation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046457

A specific and promising approach to limit inflammation and mucin iperproduction in chronic lung diseases relies on specific inhibition of nuclear Factor-κB (NF-κB) by a decoy oligonucleotide (dec-ODN). To fulfill the requirements dictated by translation of dec-ODN therapy in humans, inhalable dry powders were designed on a rational basis to provide drug protection, sustained release and to optimize pharmacological response. To this end, large porous particles (LPP) for dec-ODN delivery made of a sustained release biomaterial (poly(lactic-co-glycolic) acid, PLGA) and an "adjuvant" hydrophilic polymer (polyethylenimine, PEI) were developed and their effects on LPS-stimulated human airway epithelial cells evaluated. The composite PLGA/PEI particles containing dec-ODN (i.e., LPP(PEI)) were successfully engineered for widespread deposition in the lung and prolonged release of intact dec-ODN in vitro. LPP(PEI) caused a prolonged inhibition of IL-8 and MUC2 expression in CF human bronchial epithelial cells and human epithelial pulmonary NCI-H292 cells, respectively, as compared to naked dec-ODN. Nonetheless, as compared to previously developed LPP, the presence of PEI was essential to construct a dec-ODN delivery system able to act in mucoepidermoid lung epithelial cells. In perspective, engineering LPP with PEI may become a key factor for tuning carrier properties, controlling lung inflammation and mucin production which, in turn, can foster in vivo translation of dec-ODN therapy.