Pulmonary Delivery of Anti-microRNA Oligonucleotide and Glycyrrhizic Acid Using Ternary Peptide Micelles for the Treatment of Acute Lung Injury.

Abstract

Acute lung injury (ALI) is a devastating inflammatory disease. In lungs with inflammation, microRNA155 (miR155) induces inflammatory cytokines by inhibiting the expression of suppressor of cytokine signaling-1 (SOCS1). In addition, glycyrrhizic acid (GA) has been suggested as an anti-inflammatory drug for ALI, since it is an efficient inhibitor of nuclear factor-κB. In this study, a combined delivery system of anti-miR155 oligonucleotides (AMO155) and GA was developed with R3V6 for the treatment of ALI. R3V6s formed comicelles with cholesterol-conjugated AMO155 (AMO155c) by charge and hydrophobic interactions. GA, an amphiphilic drug, was integrated to AMO155c-R3V6 micelles, producing AMO155c-R3V6-GA ternary micelles. The size of AMO155c-R3V6-GA was smaller than that of AMO155c-R3V6, suggesting that GA integration reduced the size of the micelles effectively. In addition, AMO155c-R3V6-GA had higher delivery efficiency than AMO155c-R3V6 micelles. In the comparison of AMO155-R3V6-GA and AMO155c-R3V6-GA, cholesterol moiety of AMO155c increased the stability and delivery efficiency of the ternary micelles. For in vivo evaluation, nebulized AMO155c-R3V6-GA micelle solution were administrated into the lungs of the ALI animal models intratracheally. AMO155c-R3V6-GA micelles had improved AMO155c delivery efficiency, compared with the AMO155c-polyethylenimine complex and AMO155c-R3V6 micelles in the lungs. As a result, SOCS1 expression was increased, and proinflammatory cytokines were reduced in the AMO155c-R3V6-GA micelle groups, compared with the other groups. In conclusion, AMO155c-R3V6-GA ternary micelles may be a useful delivery system for combined therapy of AMO155 and GA for the treatment of ALI.