Polyethylenimine-engineered respirable particles delivering a decoy oligonucleotide to NF-B: a novel combination therapy for cystic fibrosis? PROGEJT FFC#23_2011

Decoy oligonucleotides (ODN) able to selectively inhibit Nuclear Factor-B (NF-B) transcriptional activity may be of great help in reducing pulmonary chronic inflammation, which is the primary cause of bronchioectasis, respiratory failure and consequent death in patients affected by cystic fibrosis (CF). ODN-based therapies are rather recent in the respiratory field and offer the advantage to selectively target the interested areas of the respiratory tract without the drawback of drug release to other non-targeted organs and tissues. Unfortunately, early on, poor cell penetration and stability of nucleic acids, low drug amounts reaching the target, inefficient penetration of mucus barriers and other lung/drug specific interactions are generally responsible for a lack of therapeutic effect. Among formulation options, inhalable large porous particles (LPP) could offer many advantages over gene delivery systems developed so far. By virtue of their porosity, LPP display an aerodynamic diameter much lower than geometric one, facilitating drug pulmonary deposition and escape from macrophage uptake. If suitably formulated, LPP may allow protection and long term delivery of the drug cargo in situ as well as dual release of ODN and helper excipients with beneficial functionalities for CF treatment. In particular, the use of poly(ethyleneimine) (PEI) in ODN pulmonary delivery for CF treatment is very intriguing in the light of PEI osmotic nature, proved antibacterial properties toward Gram (-) bacteria, and potential mucolytic properties. The aim is to test the in vivo potential of already developed dec-ODN LPP (De Stefano et al., 2011) in an animal model of airway inflammation. Furthermore, dec-ODN LPP activity will be potentiated by inserting in the composition PEI as “adjuvant” excipient and will be tested in vitro by using bronchial epithelial cells that exhibit CFTR mutations (IB3-1) and in vivo by using a lung inflammation model.