3 years ago

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

Anti-Inflammatory Effect of Anti-TNF-α SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model
Ilaria Andreana, Serge Mignani, Jean-Pierre Majoral, Magali Noiray, Camilla Foged, Claudine Delomenie, Elias Fattal, Anais Chamarat, Adam Bohr, Nicolas Tsapis, Nabil El Brahmi
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 pKa 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.

Publisher URL: http://dx.doi.org/10.1021/acs.biomac.7b00572

DOI: 10.1021/acs.biomac.7b00572

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