PEI-engineered respirable particles delivering a decoy oligonucleotide to NF-κB: inhibiting MUC2 expression in LPS-stimulated airway epithelial cells.
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.
Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy. ungaro@unina.it
Francesca
F
Ungaro
Daniela
D
De Stefano
Concetta
C
Giovino
Alessia
A
Masuccio
Agnese
A
Miro
Raffaella
R
Sorrentino
Rosa
R
Carnuccio
Fabiana
F
Quaglia
D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D055262:Mucin-2 / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry*
D016209:Interleukin-8; D008070:Lipopolysaccharides; C524625:MUC2 protein, human; D055262:Mucin-2; D016328:NF-kappa B; D009841:Oligonucleotides; D011094:Polyethyleneimine