NF-kB plays a prominent role in orchestrating the airway inflammatory response in several diseases, including cystic fibrosis [1]. The specific inhibition of NF-kB by decoy oligonucleotides delivered in the lung may limit the progression of inflammation [2], although rationally designed systems are needed to control drug release and optimize pharmacological response. In this regard, here we have developed and tested in vivo an inhalable dry powder for prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPP) based on poly(lactic-coglycolic) acid (PLGA). First, LPP containing dec-ODN (dec-ODN LPP) have been engineered to meet aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release and to preserve its structural integrity in lung lining fluids. Then, we have investigated the effects of dec-ODN LPP in a rat model of lung inflammation induced by intra-tracheal aerosolization of LSP from P. aeruginosa. The results show that a single intratracheal insufflation of dec-ODN LPP significantly prevented the neutrophil infiltration induced by LPS up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate by dec-ODN LPP was associated with a significant reduction of NF-κB/DNA binding activity as well as interleukin-6, interleukin-8 and mucin-2 mRNA expression in lung homogenates. Taken together, our findings show that dec-ODN LPP may provide a new strategy for local treatment of inflammation associated with lung diseases. 1.Park GY and Christman JW. Nuclear factor kappa B is a promising therapeutic target in inflammatory lung disease. Curr Drug Targets. 2006 Jun;7(6):661-8. 2.Cabrini G et al., Targeting transcription factor activity as a strategy to inhibit pro-inflammatory genes involved in cystic fibrosis: decoy oligonucleotides and low-molecular weight compounds. Curr Med Chem. 2010;17(35):4392-404.
A decoy oligonucleotide to NF-κB delivered through inhalable particles inhibits the lung inflammation induced by LPS in rat / Daniela De, Stefano; Ciro, Coletta; D'EMMANUELE DI VILLA BIANCA, Roberta; Lucia, Falcone; Ivana, D'Angelo; Ungaro, Francesca; Quaglia, Fabiana; Carnuccio, Rosa; Sorrentino, Raffaella. - (2013), pp. 401-401. (Intervento presentato al convegno 36° CONGRESSO NAZIONALE DELLA SOCIETÀ ITALIANA DI FARMACOLOGIA Il ruolo della RICERCA farmacologica per la CRESCITA e la SALUTE in Italia tenutosi a Torino nel 23-26 ottobre 2013).
A decoy oligonucleotide to NF-κB delivered through inhalable particles inhibits the lung inflammation induced by LPS in rat
D'EMMANUELE DI VILLA BIANCA, ROBERTA;UNGARO, FRANCESCA;QUAGLIA, FABIANA;CARNUCCIO, ROSA;SORRENTINO, RAFFAELLA
2013
Abstract
NF-kB plays a prominent role in orchestrating the airway inflammatory response in several diseases, including cystic fibrosis [1]. The specific inhibition of NF-kB by decoy oligonucleotides delivered in the lung may limit the progression of inflammation [2], although rationally designed systems are needed to control drug release and optimize pharmacological response. In this regard, here we have developed and tested in vivo an inhalable dry powder for prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPP) based on poly(lactic-coglycolic) acid (PLGA). First, LPP containing dec-ODN (dec-ODN LPP) have been engineered to meet aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release and to preserve its structural integrity in lung lining fluids. Then, we have investigated the effects of dec-ODN LPP in a rat model of lung inflammation induced by intra-tracheal aerosolization of LSP from P. aeruginosa. The results show that a single intratracheal insufflation of dec-ODN LPP significantly prevented the neutrophil infiltration induced by LPS up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate by dec-ODN LPP was associated with a significant reduction of NF-κB/DNA binding activity as well as interleukin-6, interleukin-8 and mucin-2 mRNA expression in lung homogenates. Taken together, our findings show that dec-ODN LPP may provide a new strategy for local treatment of inflammation associated with lung diseases. 1.Park GY and Christman JW. Nuclear factor kappa B is a promising therapeutic target in inflammatory lung disease. Curr Drug Targets. 2006 Jun;7(6):661-8. 2.Cabrini G et al., Targeting transcription factor activity as a strategy to inhibit pro-inflammatory genes involved in cystic fibrosis: decoy oligonucleotides and low-molecular weight compounds. Curr Med Chem. 2010;17(35):4392-404.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
