Biodegradable particles for local and prolonged delivery of an oligonucleotide decoy to nuclear factor-kB in the lung

NF-kB blockade by decoy oligonucleotides (ODNs) able to interfere with NF-kB transcriptional activity may be of great help in limiting the progression of CF lung chronic inflammation. Although data proving the validity of this approach are just emerging, early studies on CF airway epithelial cell lines are encouraging. Major concerns arise from the need of appropriate systems for ODN inhalation, that are able to efficiently target the desired region of the lungs, protect the ODN in the biological environment and release it in a sustained manner. The technological approaches currently adopted for lung delivery of ODNs reliy on the use of lipidic nanoparticles or cationic liposomes, providing new formulation options for dispersed liquid droplet dosage forms (i.e., bulky, expensive and more time-consuming nebulizers) with poor control over ODN release rate. Prompted by this, we are currently developing respirable dry powders, for prolonged pulmonary delivery of a decoy ODN to NF-kB (dec-ODN), consisting of biodegradable large porous particles (LPP) based on poly(lactic-co-glycolic) acid (PLGA). The effects of dec-ODN LPP on NF-kB/DNA binding activity as well as IL-6 and IL-8 mRNA levels were studied on DF508 CFTR-mutated human bronchial epithelial cells stimulated with LPS from P. aeruginosa for 24 and 72 h. Finally, the effects of intratracheally administered naked dec-ODN or dec-ODN LPP on neutrophil lung recruitment induced by LPS from P. aeruginosa at 6, 24 and 72 h were investigated in a rat model of airway inflammation.