277727 siRNA-Dendrimer Nanocarriers for the Lung Epithelium: In Vitro Transfection and Aerosol Formulation

Thursday, November 1, 2012: 1:50 PM
407 (Convention Center )
Denise S. Conti, Daniel Brewer, Jordan Grashik and Sandro R. P. da Rocha, Chemical Engineering and Materials Science, Wayne State University, Detroit, MI

RNA interference (RNAi) is a gene therapy approach that works by silencing the expression of target genes in a post-transcriptional manner.  Small interfering RNA (siRNA) therapeutics have several advantages over small molecules drugs and proteins, as for example the rapid identification and optimization of lead compounds, and the potential to inhibit all targets, including those considered ‘non-druggable’.  There are many potential opportunities in formulating siRNA therapeutics in oral inhalation (OI) devices, as it may provide for a direct and non-invasive means of targeting the lung tissue.  However, there are many challenges in the development of OI formulations for the efficient delivery of siRNA to the lungs, and in the design of siRNA-based nanocarriers capable of overcoming the extra and intracellular barriers present before siRNA reach the cytosol in relevant cell populations in the lungs.

In this work we report (i) the preparation of siRNA-dendrimer complexes and their characterization by dynamic light scattering, SEM, TEM and AFM, (ii) the formulation of those nanocarriers in portable inhalers, and (iii) their gene silencing efficiency in lung epithelial cell models.  Airway (Calu-3) and alveolar (A549) cell lines that stably express eGFP were developed and the gene knockdown ability of the nanocarriers as a function of relevant variables such as N/P ratio evaluated on those cell lines.  Our studies show that with the appropriate particle engineering technology, siRNA-dendrimer nanocarriers can be formulated in portable OI devices that possess aerosol characteristics conducive to deep lung deposition.

The relevance of this work stems from the fact that siRNA-based gene therapy is a promising approach to treat a variety of medically relevant pulmonary disorders, including lung cancer, pulmonary tuberculosis, cystic fibrosis, and asthma, and also due to the fact that portable inhalers are the most widely used devices for the non-invasive, regional targeting of such lung diseases.

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See more of this Session: Bionanotechnology for Gene and Drug Delivery II
See more of this Group/Topical: Nanoscale Science and Engineering Forum