Open Access Dissertation
Date of Award
Chemical Engineering and Materials Science
Sandro R. da Rocha
Gene therapy has attracted attention in the fields of medicine, pharmacy, and bionanotechnology due to the potential for treating a large number of medically relevant diseases. Oral inhalation (OI) is a promising route for the administration of therapeutics, including small molecules and biomacromolecules, such as nucleotides, peptides, and proteins, to (locally) and through (systemically) the lungs. The use of OI is especially attractive for the delivery of nucleic acids as it provides a direct and non-invasive route for targeting the lungs. Pressurized metered-dose inhalers (pMDIs), are the most commonly used OI in treatment of lung diseases and are thus promising OI devices to be used for the delivery of nucleic acids to the lungs. However, progress in the development of pMDI formulations for the delivery of DNA and siRNA to the lungs has been hampered largely by the lack of efficient nanocarriers capable of overcoming the lung structure, the extra and intracellular barriers present in the lung tissue, and formulation challenges - aerodynamic particle size, surface chemistry of the particles, and solvation forces in propellant/co-solvent mixture. In light of the challenges and opportunities described above, we propose in this work: (i) a quantitatively and systematically evaluation of the enhancement in solvation capacity of propellant hydrofluoroalkane (HFA) upon addition of co-solvent ethanol; (ii) the development of efficient HFA-based pMDIs to deliver nucleic acids to the lungs; (iii) the design of siRNA-poly(amidoamine) (PAMAM) dendrimer conjugates. We demonstrate that both DNA and siRNA can be efficiently formulated in HFA-based pMDIs upon the development of novel particle engineering strategies to overcome issues associated with their size and physical stability in the propellant. We also demonstrate that the polymer-based nanocarriers are capable of enhancing gene expression (DNA) and knockdown (siRNA) in alveolar lung epithelial cells, and they do not lose their biological activity when formulated in the propellant HFA. In conclusion, the results reported in this dissertation contribute significantly in the development of DNA- and siRNA-delivery systems and in their formulation in portable OI devices, with great potential to efficiently deliver nucleic acids to the lungs to treat medically relevant pulmonary disorders, such as COPD, asthma, virus infections, cystic fibrosis, and lung cancer.
Conti, Denise Santos, "Polymeric Nanocarriers And Their Oral Inhalation Formulations For The Regional Delivery Of Nucleic Acids To The Lungs" (2013). Wayne State University Dissertations. 756.