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

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

Research output: Contribution to journalArticle

Abstract

Background: 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.Results: To overcome this challenge, we developed a nano-based approach that uses drug loaded biodegradable nanoparticle (PLGA-PEGPS-341) to provide controlled and sustained drug delivery. The in vitro 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 in vivo 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 (Cftr-/-) lungs was determined by quantifying the changes in proteasomal activity (~2 fold decrease) and ability to rescue the Pseudomonas aeruginosa LPS (Pa-LPS) induced inflammation, which demonstrates the rescue of CF lung disease in murine model.Conclusion: 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 Pa-LPS induced CF lung disease.

Original languageEnglish (US)
Article number22
JournalJournal of Nanobiotechnology
Volume8
DOIs
StatePublished - Sep 24 2010

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Drug delivery
Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Nanoparticles
Lung
Pulmonary diseases
Proteasome Endopeptidase Complex
Pharmaceutical Preparations
Pseudomonas aeruginosa
Lung Diseases
Pharmacokinetics
Whole Body Imaging
Mutation
Proteasome Inhibitors
Kinetics
Optical Imaging
Threonine
Drug Delivery Systems
Regulator Genes
Biodegradation

ASJC Scopus subject areas

  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering
  • Applied Microbiology and Biotechnology
  • Medicine (miscellaneous)
  • Pharmaceutical Science

Cite this

Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis. / Vij, Neeraj; Min, Taehong; Marasigan, Rhul; Belcher, Christopher N.; Mazur, Steven; Ding, Hong; Yong, Ken Tye; Roy, Indrajit.

In: Journal of Nanobiotechnology, Vol. 8, 22, 24.09.2010.

Research output: Contribution to journalArticle

Vij, Neeraj ; Min, Taehong ; Marasigan, Rhul ; Belcher, Christopher N. ; Mazur, Steven ; Ding, Hong ; Yong, Ken Tye ; Roy, Indrajit. / Development of PEGylated PLGA nanoparticle for controlled and sustained drug delivery in cystic fibrosis. In: Journal of Nanobiotechnology. 2010 ; Vol. 8.
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AU - Mazur, Steven

AU - Ding, Hong

AU - Yong, Ken Tye

AU - Roy, Indrajit

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