(324d) Polyplexes In Propellant-Based Oral Inhalation Formulations: A Non-Invasive Approach for the Delivery of Genes to the Lungs

Pressurized metered-dose inhalers (pMDIs) are the least expensive oral inhalation (OI) devices for the regional delivery of small therapeutics to the lungs, and the most widely used inhalation formulations in the market.  More recently, pMDIs have received renewed attention as it has been demonstrated that inhalation therapy also holds promise for the delivery of therapeutic biomolecules including proteins, peptides, and nucleotides to and through (systemically) the lungs.  However, most therapeutics have very limited solubility in the hydrophobic and lipophobic propellants used in pMDIs, typically requiring their formulation as suspensions.  Another challenge arises when attempting to deliver nanotherapeutics to the lungs, as in the case of polymeric nanoparticles for gene delivery applications, as the aerosol size for optimum lung deposition falls within the micron range.  The extracellular barriers, including mucus layer, and lung surfactant, which are present in the pulmonary epithelium, are also hindrances that need to be overcome for efficient delivery of genes to the lungs.  In this presentation we will discuss the ability of chitosan-based polyplexes to transfect airway and epithelial lung cells in vitro.  The effect of the physical properties of the polyplexes and their interaction with the extracellular environment will be discussed and correlated with their transfection efficiency. The formulation of the polyplexes in pMDIs and their aerosol characteristics will also be discussed.

Key Words: Pulmonary Gene Delivery, Pressurized-Metered Dose Inhalers, Polyplexes, Hydrofluoroalkanes, In Vitro Transfection, Mucus Layer, Lung Surfactant.