(16d) Ternary Particles for Sustained Gene Delivery

Targeted gene delivery via the lungs has the potential to be an attractive approach for systemic or local gene delivery. However, preventing rapid clearance of the non-viral vectors by macrophages remains problematic. In this study we combine two approaches to prevent rapid clearance and uptake of our DNA molecules by macrophages in the lung. The first is to entrap the plasmid DNA in to large particles which have been shown to escape clearance by alveolar macrophages. These particles were prepared with a highly porous structure to ensure low mass density for efficient aerosol delivery to the lower regions of the lung. The DNA is entrapped in a pegylated degradable co-polymer that simultaneously reduces opsonization and clearance by macrophages because of the stealth properties generated when the PEG portion of the co-polymer phase separates at the surface of the particles during water-in-oil-in water double emulsion solvent evaporation preparation. Several reports have indicated that naked DNA can be inactivated during entrapment in the biodegradable microparticles. To overcome this, we first complex DNA to a cationic polymer, polyethylene imine (PEI), to provide protection during entrapment in the microparticles. Preliminary results indicate that porous pegylated particles have significant potential for increasing release of gene delivery agents over longer periods of time.