Anti-Inflammatory Effect of Anti-TNF‑α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model

Inflammation is an essential component of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), or acute lung injury. Our purpose was to design efficient carriers for lung delivery of small interfering RNA (siRNA) targeting tumor necrosis factor (TNF-α) in an acute lung...

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Bibliographic Details
Published in:	Biomacromolecules Vol. 18; no. 8; pp. 2379 - 2388
Main Authors:	Bohr, Adam, Tsapis, Nicolas, Andreana, Ilaria, Chamarat, Anais, Foged, Camilla, Delomenie, Claudine, Noiray, Magali, El Brahmi, Nabil, Majoral, Jean-Pierre, Mignani, Serge, Fattal, Elias
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 14-08-2017
Subjects:	Acute Lung Injury - drug therapy Acute Lung Injury - genetics Acute Lung Injury - metabolism Acute Lung Injury - pathology Administration, Intranasal Animals Anti-Inflammatory Agents - chemistry Anti-Inflammatory Agents - pharmacology Chemical Sciences Coordination chemistry Dendrimers - chemistry Dendrimers - pharmacology Disease Models, Animal Female Gene Silencing Mice Morpholinos - chemistry Morpholinos - genetics Morpholinos - pharmacology RAW 264.7 Cells RNA, Small Interfering - chemistry RNA, Small Interfering - genetics RNA, Small Interfering - pharmacology Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - genetics
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Summary:	Inflammation is an essential component of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), or acute lung injury. Our purpose was to design efficient carriers for lung delivery of small interfering RNA (siRNA) targeting tumor necrosis factor (TNF-α) in an acute lung injury model. To achieve this goal, two different types of phosphorus-based dendrimers with either pyrrolidinium or morpholinium as terminal protonated amino groups were selected for their better biocompatibility compared to other dendrimers. Dendriplexes containing pyrrolidinium surface groups demonstrated a stronger siRNA complexation, a higher cellular uptake, and enhanced in vitro silencing efficiency of TNF-α in the lipopolysaccharide (LPS)-activated mouse macrophage cell line RAW264.7, compared to morpholinium-containing dendriplexes. The better performance of the pyrrolidium dendriplexes was attributed to their higher pK a value leading to a stronger siRNA complexation and improved protection against enzymatic degradation resulting in a higher cellular uptake. The superior silencing effect of the pyrrolidinium dendriplexes, compared to noncomplexed siRNA, was confirmed in vivo in an LPS-induced murine model of short-term acute lung injury upon lung delivery via nasal administration. These data suggest that phosphorus dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases.
ISSN:	1525-7797 1526-4602
DOI:	10.1021/acs.biomac.7b00572