Matrix systems based on biocompatible and biodegradable
polymers like the United States Food and Drug Administration (FDA)-approved
polymer poly(DL-lactide-co-glycolide
acid) (PLGA) are promising for the delivery of
small interfering RNA (
siRNA) due to favorable safety profiles, sustained release properties and improved colloidal stability, as compared to polyplexes. The purpose of this study was to design a dry
powder formulation based on cationic
lipid-modified PLGA nanoparticles intended for treatment of severe
lung diseases by pulmonary delivery of
siRNA. The cationic
lipid dioleoyltrimethylammoniumpropane (
DOTAP) was incorporated into the PLGA matrix to potentiate the gene silencing efficiency. The gene knock-down level in vitro was positively correlated to the weight ratio of
DOTAP in the particles, and 73% silencing was achieved in the presence of 10% (v/v) serum at 25% (w/w)
DOTAP. Optimal properties were found for nanoparticles modified with 15% (w/w)
DOTAP, which reduced the gene expression with 54%. This formulation was spray-dried with
mannitol into nanocomposite microparticles of an aerodynamic size appropriate for lung deposition. The spray-drying process did not affect the physicochemical properties of the readily re-dispersible nanoparticles, and most importantly, the in vitro gene silencing activity was preserved during spray-drying. The
siRNA content in the
powder was similar to the theoretical loading and the
siRNA was intact, suggesting that the
siRNA is preserved during the spray-drying process. Finally, X-ray
powder diffraction analysis demonstrated that
mannitol remained in a crystalline state upon spray-drying with PLGA nanoparticles suggesting that the
sugar excipient might exert its stabilizing effect by sterical inhibition of the interactions between adjacent nanoparticles. This study demonstrates that spray-drying is an excellent technique for engineering dry
powder formulations of
siRNA nanoparticles, which might enable the local delivery of biologically active
siRNA directly to the lung tissue.