‘Smart‘ non-viral Delivery Systems for Targeted Delivery of RNAi to the Lungs

Ramsey, Joanne M.; Hibbitts, Alan; Barlow, James W.; Kelly, Ciara; Sivadas, Neeraj; Cryan, Sally‐Ann

doi:10.4155/tde.12.133

Cited by 12 publications

(11 citation statements)

References 130 publications

(109 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…43,44 These approaches might also prove of use for hVDAC1-siRNA targeting lung cancer when introduced via appropriate delivery systems, such as lipid- and polymer-based vectors, formulated for inhalation. 45,46 …”

Section: Discussionmentioning

confidence: 99%

Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

Arif

Vasilkovsky

Refaely

et al. 2014

Molecular Therapy - Nucleic Acids

120

145

View full text Add to dashboard Cite

Alterations in cellular metabolism and bioenergetics are vital for cancer cell growth and motility. Here, the role of the mitochondrial protein voltage-dependent anion channel (VDAC1), a master gatekeeper regulating the flux of metabolites and ions between mitochondria and the cytoplasm, in regulating the growth of several cancer cell lines was investigated by silencing VDAC1 expression using small interfering RNA (siRNA). A single siRNA specific to the human VDAC1 sequence at nanomolar concentrations led to some 90% decrease in VDAC1 levels in the lung A549 and H358, prostate PC-3, colon HCT116, glioblastoma U87, liver HepG2, and pancreas Panc-1 cancer cell lines. VDAC1 silencing persisted 144 hours post-transfection and resulted in profound inhibition of cell growth in cancer but not in noncancerous cells, with up to 90% inhibition being observed over 5 days that was prolonged by a second transfection. Cells expressing low VDAC1 levels showed decreased mitochondrial membrane potential and adenoside triphosphate (ATP) levels, suggesting limited metabolite exchange between mitochondria and cytosol. Moreover, cells silenced for VDAC1 expression showed decreased migration, even in the presence of the wound healing accelerator basic fibroblast growth factor (bFGF). VDAC1-siRNA inhibited cancer cell growth in a Matrigel-based assay in host nude mice. Finally, in a xenograft lung cancer mouse model, chemically modified VDAC1-siRNA not only inhibited tumor growth but also resulted in tumor regression. This study thus shows that VDAC1 silencing by means of RNA interference (RNAi) dramatically inhibits cancer cell growth and tumor development by disabling the abnormal metabolic behavior of cancer cells, potentially paving the way for a more effective pipeline of anticancer drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

Arif

Vasilkovsky

Refaely

et al. 2014

Molecular Therapy - Nucleic Acids

120

145

View full text Add to dashboard Cite

show abstract

“…Indeed, many efforts have been made so as to improve gene delivery performances, such as considering the use of specific targeting ligands into the vector, in order to optimize gene delivery to the appropriate target cells and reduce the total dose of vector required. Similar hurdles hold for delivery of small interfering RNA (siRNA) to the lung cells [19,20].…”

Section: Gene Delivery To the Lungmentioning

confidence: 99%

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

Gioia

Trapani

Castellani

et al. 2015

Pulmonary Pharmacology & Therapeutics

View full text Add to dashboard Cite

“…Local delivery is particularly promising as an approach for oligonucleotide therapeutics targeting respiratory diseases. This is especially true for episodes of acute pulmonary inflammation, including acute asthmatic episodes and pathogenic respiratory conditions such as acute respiratory distress syndrome (ARDS) [ 7 , 8 ]. The urgent need to mitigate the effects of respiratory viruses has become especially relevant with the emergence of the COVID-19 pandemic.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

et al. 2020

Self Cite

View full text Add to dashboard Cite

Inhalation offers a means of rapid, local delivery of siRNA to treat a range of autoimmune or inflammatory respiratory conditions. This work investigated the potential of a linear 10 kDa Poly(ethylene glycol) (PEG)-modified 25 kDa branched polyethyleneimine (PEI) (PEI-LPEG) to effectively deliver siRNA to airway epithelial cells. Following optimization with anti- glyceraldehyde 3-phosphate dehydrogenase (GAPDH) siRNA, PEI and PEI-LPEG anti-IL8 siRNA nanoparticles were assessed for efficacy using polarised Calu-3 human airway epithelial cells and a twin stage impinger (TSI) in vitro lung model. Studies were then advanced to an in vivo lipopolysaccharide (LPS)-stimulated rodent model of inflammation. In parallel, the suitability of the siRNA-loaded nanoparticles for nebulization using a vibrating mesh nebuliser was assessed. The siRNA nanoparticles were nebulised using an Aerogen® Pro vibrating mesh nebuliser and characterised for aerosol output, droplet size and fine particle fraction. Only PEI anti-IL8 siRNA nanoparticles were capable of significant levels of IL-8 knockdown in vitro in non-nebulised samples. However, on nebulization through a TSI, only PEI-PEG siRNA nanoparticles demonstrated significant decreases in gene and protein expression in polarised Calu-3 cells. In vivo, both anti-CXCL-1 (rat IL-8 homologue) nanoparticles demonstrated a decreased CXCL-1 gene expression in lung tissue, but this was non-significant. However, PEI anti-CXCL-1 siRNA-treated rats were found to have significantly less infiltrating macrophages in their bronchoalveolar lavage (BAL) fluid. Overall, the in vivo gene and protein inhibition findings indicated a result more reminiscent of the in vitro bolus delivery rather than the in vitro nebulization data. This work demonstrates the potential of nebulised PEI-PEG siRNA nanoparticles in modulating pulmonary inflammation and highlights the need to move towards more relevant in vitro and in vivo models for respiratory drug development.

show abstract

‘Smart‘ non-viral Delivery Systems for Targeted Delivery of RNAi to the Lungs

Cited by 12 publications

References 130 publications

Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

In Vitro and In Vivo Assessment of PEGylated PEI for Anti-IL-8/CxCL-1 siRNA Delivery to the Lungs

Contact Info

Product

Resources

About