Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Kelly, Ciara; Yadav, Awadh Bihari; Lawlor, Ciaran; Nolan, Kevin B.; O’Dwyer, Joanne; Greene, Catherine M.; McElvaney, Noel G.; Sivadas, Neeraj; Ramsey, Joanne M.; Cryan, Sally‐Ann

doi:10.1021/mp500473d

Cited by 20 publications

(23 citation statements)

References 30 publications

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“…4). Our results are in line with previously published reports and further provide evidence for the central role of NF-kB in ALI and immunity [9, 10]. …”

Section: Discussionsupporting

confidence: 93%

Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

Song

Zhao

et al. 2016

BMC Physiol

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BackgroundTo investigate the anti-inflammatory effects of specific small interfering RNA targeting NF-κB on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats.MethodAcute lung injury was induced in Sprague-Dawley rats by intraperitoneal injection with LPS (5 mg/kg), followed by immediate intratracheal instillation of siRNA targeting NF-κB p65 (40 μg/ml). Animals in each group were sacrificed at 1 h or 8 h after the instillation. Pulmonary histological changes were evaluated by hematoxylin-eosin staining. The levels of NF-κB and TNF-α were measured by qRT-PCR. Expressions of NF-κB in lung cells and TNF-α in bronchoalveolar lavage fluid (BALF) were determined by western blot analysis and enzyme-linked immunosorbent assay (ELISA) respectively.ResultsLPS administration reduced the rectal temperature and white blood cell counts at 1 h, increased lung wet/dry weight ratios, caused evident lung histopathological injury, and increased the detectable transcript and cytokine levels of TNF-α in lung tissue in BALF. siRNA targeting of NF-κB p65 effectively abrogated the expression of NF-κB p65 in lung cells and, aside from rectal temperatures, ameliorated all changes induced by LPS.ConclusionsNF-κB knockdown exerts anti-inflammatory effects on LPS-induced ALI especially in the initial phase, which may be due in part to reduced levels of the proinflammatory cytokine TNF-α. NF-κB siRNA’s rapidity and effectiveness to abrogate ALI development may provide an effective therapeutic method with future clinical applications.

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“…4). Our results are in line with previously published reports and further provide evidence for the central role of NF-kB in ALI and immunity [9, 10]. …”

Section: Discussionsupporting

confidence: 93%

Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

Song

Zhao

et al. 2016

BMC Physiol

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“…Statistical significance was determined by two-way analysis of variance followed by Bonferroni post-hoc test (*p <0.05) versus empty microparticle counterparts. Reproduced, with permission, from [80]. For accurate analysis, NP must be correctly assigned to individual cells (color coded).…”

Section: Discussionmentioning

confidence: 99%

“…CLSM, while providing detailed qualitative intracellular trafficking information, was also limited in terms of quantitative analysis of microparticle uptake because of the subjectivity involved in cell selection, counting errors, and the limited number of samples that can be analyzed. The information from HCA study has been used to harness PLG-based MPs for delivery of a range of therapeutic cargoes requiring intracellular delivery to macrophages, including short hairpin (sh)RNA, siRNA, and miRNA [80] (Figure 7). Thus, HCA offers a useful additional tool to discriminate accurately intracellular delivery of particles across a range of particle sizes.…”

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confidence: 99%

High-content analysis for drug delivery and nanoparticle applications

Brayden

Cryan

Dawson

et al. 2015

Drug Discovery Today

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Publication information Drug Discovery Today, 20 (8): 942-957Publisher Elsevier Item record/more information http://hdl.handle.net/10197/6636 Publisher's statementThis is the author's version of a work that was accepted for publication in Drug Discovery Today. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Drug Discovery Today, 20 (8), (2015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 26A c c e p t e d M a n u s c r i p t Sally-Ann CryanSally-Ann Cryan has a pharmacy degree and a PhD in pharmaceutics ( Jeremy SimpsonJeremy Simpson carried out his PhD at the University of Warwick, followed postdoctoral work at the Scripps Research Institute in San Diego, and the Imperial Cancer Research Fund in London. After 9 years as a staff member at the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), he was appointed as professor of cell biology at UCD, in 2008. He currently applies high-throughput imaging technologies to study subcellular transport pathways and the internalization routes taken by nanoparticles in cells. He runs the UCD Cell Screening Laboratory and is the author of more than 80 publications.High-content analysis (HCA) provides quantitative multiparametric cellular fluorescence data. From its origins in discovery toxicology, it is now addressing fundamental questions in drug delivery. Nanoparticles (NPs), polymers, and intestinal permeation enhancers are being harnessed in drug delivery systems to modulate plasma membrane properties and the intracellular environment. Identifying comparative mechanistic cytotoxicity on sublethal events is crucial to expedite the development of such systems. NP uptake and intracellular routing pathways are also being dissected using chemical and genetic perturbations, with the potential to assess the intracellular fate of targeted and untargeted particles in vitro. As we discuss here, HCA is set to make a major impact in preclinical delivery research by elucidating the intracellular pathways of NPs and the in vitro mechanistic-based toxicology of formulation constituents. A brief recap of cytotoxicity assaysIn vitro cell-based assays have long been used to assess the cytotoxic effects of drug exposure [1]. Cells undergoing acute necrosis swell and lose metabolic capacity, thereby losing the capacity to maintain a barrier to the extracellular space and the ability ...

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“…the surfactant and mucus layers), and retard endolysosomal degradation. For example, polymeric nanoparticles made of either chitosan [29] or poly (ethylenimine)/poly (ethylene glycol)-poly(ethylenimine) (PEI/PEG-PEI) [30] and PLGA microparticles [31] increase the bioavailability and delivery efficiency of the encapsulated siRNA. Intratracheal administration of chitosan nanoparticles carrying siRNA specific for green fluorescent protein (EGFP) achieves greater gene silencing compared to those of mismatched control nanoparticles, naked siRNA, and untreated control groups in a EGFP-expressing murine model, indicating an advantage of chitosan-siRNA nanoparticles [32].…”

Section: Rationales For Use Of Nanotechnology In Pulmonary Deliverymentioning

confidence: 99%

Nano-Therapeutics for the Lung: State-of-the-Art and Future Perspectives

Iyer¹,

Hsia²,

Nguyen

2015

CPD

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Inhalation of aerosolized compounds is a popular, non-invasive route for the targeted delivery of therapeutic molecules to the lung. Various types of nanoparticles have been used as carriers to facilitate drug uptake and intracellular action in order to treat lung diseases and/or to facilitate lung repair and growth. These include polymeric nanoparticles, liposomes, and dendrimers, among many others. In addition, nanoparticles are sometimes used in combination with small molecules, cytokines, growth factors, and/or pluripotent stem cells. Here we review the rationale and state-of-the-art nanotechnology for pulmonary drug delivery, with particular attention to new technological developments and approaches as well as the challenges associated with them, the emerging advances, and opportunities for future development in this field.

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Therapeutic Aerosol Bioengineering of siRNA for the Treatment of Inflammatory Lung Disease by TNFα Gene Silencing in Macrophages

Cited by 20 publications

References 30 publications

Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

High-content analysis for drug delivery and nanoparticle applications

Nano-Therapeutics for the Lung: State-of-the-Art and Future Perspectives

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