TY - JOUR

T1 - ANTI-INFLAMMATORY EFFECT OF ANTI-TNF-ALPHA siRNA CATIONIC PHOSPHOROUS DENDRIMERS NANOCOMPLEXES ADMINISTERED INTRANASALLY IN A MURINE ACUTE LUNG INJURY MODEL

AU - Bohr, Adam

AU - Tsapis, Nicolas

AU - Andreana, Ilaria

AU - Chamarat, Anais

AU - Foged, Camilla

AU - Delomenie, Claudine

AU - Noiray, Magali

AU - El Brahmi, Nabil

AU - Majoral, Jean-Pierre

AU - Mignani, Serge

AU - Fattal, Elias

PY - 2017/6/21

Y1 - 2017/6/21

N2 - 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)alpha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-alpha 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 non-complexed 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 phosphorous dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases.

AB - 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)alpha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-alpha 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 non-complexed 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 phosphorous dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases.

U2 - 10.1021/acs.biomac.7b00572

DO - 10.1021/acs.biomac.7b00572

M3 - Journal article

C2 - 28639789

VL - 18

SP - 2379

EP - 2388

JO - Biomacromolecules

JF - Biomacromolecules

SN - 1525-7797

IS - 8

ER -