(560e) Dendrimer-siRNA Complexes and Their Aerosol Formulation for Lung Delivery Applications
AIChE Annual Meeting
Wednesday, November 6, 2013 - 4:27pm to 4:45pm
RNA interference (RNAi) promotes silencing of gene expression in a post-transcriptional manner. RNAi-is a potential therapeutic in the treatment of several medically relevant pulmonary diseases, such as lung cancer, cystic fibrosis, asthma, chronic obstructive pulmonary disease, respiratory syncytial virus, and severe acute respiratory syndrome viral infection, and there are several ongoing clinical trials related to lung and siRNA. However, progress in this area has been hindered largely by the lack of efficient carriers capable of overcoming the lung architecture, extra and intracellular barriers present in the lung tissue to the efficient delivery of siRNA to the cell cytosol, and also due to formulation challenges.
In this work we report the preparation and characterization of dendriplexes between siRNA and poly(amidoamine) (PAMAM) dendrimers, and their in vitro gene knockdown efficiency in a model lung alveolar epithelium cell line stably expressing eGFP. We also show strategies to formulate and deliver siRNA and their dendriplexes via oral inhalation administration using pressurized metered-dose inhalers (pMDIs). We study the gene knock-down efficiency of the nanocarriers as a function of the N/P ratio and also examine the effect of the propellant environment on siRNA activity. We observed that the knockdown efficiency was not affected when the siRNA was kept in contact with the propellant during long periods of time. Finally, we show that the proposed particle engineering strategies are effective in producing aerosols conducive to the delivery of siRNA in the form of dendriplexes to the deep lungs. The respirable fraction of the proposed particle engineering strategies was determined to be at least 64%, with mass median aerodynamic diameter close to the 2 mm target. This work is relevant as it demonstrates the potential of formulating and delivering siRNA-nanocarrier complexes to the lungs using the inexpensive and widely employed portable inhalers, the pMDIs.