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Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis

By Mazur Steven, Belcher Christopher N, Marasigan Rhul, Min Taehong, Vij Neeraj, Ding Hong, Yong Ken-Tye and Roy Indrajit


<p>Abstract</p> <p>Background</p> <p>The mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene results in CF. The most common mutation, ΔF508-CFTR, is a temperature-sensitive, trafficking mutant with reduced chloride transport and exaggerated immune response. The ΔF508-CFTR is misfolded, ubiquitinated, and prematurely degraded by proteasome mediated- degradation. We recently demonstrated that selective inhibition of proteasomal pathway by the FDA approved drug PS-341 (pyrazylcarbonyl-Phe-Leuboronate, a.k.a. Velcade or bortezomib) ameliorates the inflammatory pathophysiology of CF cells. This proteasomal drug is an extremely potent, stable, reversible and selective inhibitor of chymotryptic threonine protease-activity. The apprehension in considering the proteasome as a therapeutic target is that proteasome inhibitors may affect proteostasis and consecutive processes. The affect on multiple processes can be mitigated by nanoparticle mediated PS-341 lung-delivery resulting in favorable outcome observed in this study.</p> <p>Results</p> <p>To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEG<sup>PS-341</sup>) to provide controlled and sustained drug delivery. The <it>in vitro </it>release kinetics of drug from nanoparticle was quantified by proteasomal activity assay from days 1-7 that showed slow drug release from day 2-7 with maximum inhibition at day 7. For <it>in vivo </it>release kinetics and biodistribution, these drug-loaded nanoparticles were fluorescently labeled, and administered to C57BL6 mice by intranasal route. Whole-body optical imaging of the treated live animals demonstrates efficient delivery of particles to murine lungs, 24 hrs post treatment, followed by biodegradation and release over time, day 1-11. The efficacy of drug release in CF mice (<it>Cftr<sup>-/-</sup></it>) lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease) and ability to rescue the <it>Pseudomonas aeruginosa </it>LPS (<it>Pa</it>-LPS) induced inflammation, which demonstrates the rescue of CF lung disease in murine model.</p> <p>Conclusion</p> <p>We have developed a novel drug delivery system to provide sustained delivery of CF "correctors" and "anti-inflammatories" to the lungs. Moreover, we demonstrate here the therapeutic efficacy of nano-based proteostasis-modulator to rescue <it>Pa-LPS </it>induced CF lung disease.</p

Topics: Biotechnology, TP248.13-248.65, Chemical technology, TP1-1185, Technology, T, DOAJ:Biotechnology, DOAJ:Life Sciences, DOAJ:Biology and Life Sciences, Medical technology, R855-855.5
Publisher: BioMed Central
Year: 2010
DOI identifier: 10.1186/1477-3155-8-22
OAI identifier: oai:doaj.org/article:23f700e40bf8463e9135c50a44514464
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