Aerosol delivery of robust polyethyleneimine-DNA complexes for gene therapy and genetic immunization

Aerosol delivery of plasmid DNA to the lungs offers the possibility of dire ct application of gene preparations to pulmonary surfaces as a means of tre ating a variety of genetic pulmonary disorders. However, the process of jet nebulization rapidly degrades naked DNA, viral vectors, and many lipid-bas ed formulations. While complexing DNA with cationic lipids has been shown t o significantly stabilize plasmid DNA, losses of biological activity often occur during nebulization, severely limiting the efficiency of aerosol deli very of many such complexes. In conjunction with the design of aerosol deli very systems appropriate for DNA delivery, we have developed formulations u sing polyethyleneimine (PEI, a polycationic polymer) and DNA that result in a high level of pulmonary transfection (10- to 100-fold greater than many cationic lipids) and are stable during nebulization. In addition, these PEI -based formulations exhibit a high degree of specificity for the lungs. The properties of PEI-based formulations that make them resistant to nebulizat ion and efficient as DNA delivery vectors for pulmonary sites have been inv estigated. Potential applications of this technology, including the use of aerosolized PEI-DNA for genetic immunization, are discussed.