Oligonucleotide decoy to NF-κB slowly released from PLGA microspheres reduces chronic inflammation in rat

Nuclear factor-kappa B (NF-kappa B) plays a key role in the expression of several genes involved in the immune and inflammatory process. Previously, we demonstrated that NF-kappa B activation can be significantly inhibited by a double stranded oligodeoxynucleotide (ODN). Nevertheless, the therapeutic use of ODN requires a delivery system able to improve poor crossing of cell membranes and rapid in vivo enzymatic degradation. Poly(D,L-lactide-co-glycolide) (PLGA) microspheres can increase ODN stability in biological environment and release the encapsulated drug in long time frames. Here, we used a decoy ODN against NF-kappa B and we investigated its effect, when administered in naked form or when delivered by PLGA micropsheres. in a rat model of chronic inflammation. The subcutaneous implant of lambda-carrageenin-soaked sponges caused leukocyte infiltration and formation of granulation tissue which were inhibited up to 15 days by co-injection of microspheres releasing decoy ODN whereas naked decoy ODN showed this effect only up to 5 days. Molecular analysis performed on granulation tissue demonstrated an inhibition of NF-kappa B activation correlated to a decrease of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression. Our results suggest that microspheres could be an useful tool to improve pharmacokinetics of decoy ODN and may represent a strategy to inhibit NF-kappa B activation in chronic inflammation. (C) 2009 Elsevier Ltd. All Fights reserved.