Acid-Sensitive Sheddable PEGylated PLGA Nanoparticles Increase the Delivery of TNF-[alpha] siRNA in Chronic Inflammation Sites

Abstract

There has been growing interest in utilizing small interfering RNA (siRNA) specic to pro-inammatory cytokines, such as tumor necrosis factor- ( TNF-), in chronic inammation therapy. However, delivery systems that can increase the distribution of the siRNA in chronic inammation sites after intravenous administration are needed. Herein we report that innovative functionalization of the surface of siRNA-incorporated poly (lactic-co-glycolic) acid (PLGA) nanoparticles signicantly increases the delivery of the siRNA in the chronic inammation sites in a mouse model. The TNF- siRNA incorporated PLGA nanoparticles were prepared by the standard double emulsion method, but using stearoyl-hydrazone-polyethylene glycol 2000, a unique acid-sensitive surface active agent, as the emulsifying agent, which renders (i) the nanoparticles PEGylated and (ii) the PEGylation sheddable in low pH environment such as that in chronic inammation sites. In a mouse model of lipopolysaccharide-induced chronic inammation, the acid-sensitive sheddable PEGylated PLGA nanoparticles showed signicantly higher accumulation or distribution in chronic inammation sites than PLGA nanoparticles prepared with an acid-insensitive emulsifying agent (i.e., stearoyl-amide-polyethylene glycol 2000) and signicantly increased the distribution of the TNF- siRNA incorporated into the nanoparticles in inamed mouse foot.