Oligonucleotide decoy to NF-kappaB slowly released from PLGA microspheres reduces chronic inflammation in rat.
Nuclear factor-kappaB (NF-kappaB) plays a key role in the expression of several genes involved in the immune and inflammatory process. Previously, we demonstrated that NF-kappaB 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-kappaB and we investigated its effect, when administered in naked form or when delivered by PLGA microspheres, 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-kappaB 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-kappaB activation in chronic inflammation.
Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy. dadestef@unina.it
Daniela
D
De Stefano
Giuseppe
G
De Rosa
Maria Chiara
MC
Maiuri
Francesca
F
Ungaro
Fabiana
F
Quaglia
Teresa
T
Iuvone
Maria Pia
MP
Cinelli
Maria Immacolata
MI
La Rotonda
Rosa
R
Carnuccio
D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D024202:Electrophoretic Mobility Shift Assay; D006097:Granulation Tissue / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D008863:Microspheres; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D054735:Phosphorothioate Oligonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D004337:Drug Carriers; D016328:NF-kappa B; D054735:Phosphorothioate Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D009569:Nitric Oxide; D019344:Lactic Acid; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat