This article reviews the pulmonary route of administration, aerosol delivery devices, characterization of pulmonary drug delivery systems, and discusses the rationale for inhaled delivery of siRNA. Diseases with known protein malfunctions may be mitigated through the use of siRNA therapeutics. The inhalation route of administration provides local delivery of siRNA therapeutics for the treatment of various pulmonary diseases, however barriers to pulmonary delivery and intracellular delivery of siRNA exists. siRNA loaded nanocarriers can be used to overcome the barriers associated with the pulmonary route, such as anatomical barriers, mucociliary clearance, and alveolar macrophage clearance. Apart from naked siRNA aerosol delivery, previously studied siRNA carrier systems comprise of lipidic, polymeric, peptide, or inorganic origin. Such siRNA delivery systems formulated as aerosols can be successfully delivered via an inhaler or nebulizer to the pulmonary region. Preclinical animal investigations of inhaled siRNA therapeutics rely on intratracheal and intranasal siRNA and siRNA nanocarrier delivery. Aerosolized siRNA delivery systems may be characterized using in vitro techniques, such as dissolution test, inertial cascade impaction, delivered dose uniformity assay, laser diffraction, and laser Doppler velocimetry. The ex vivo techniques used to characterize pulmonary administered formulations include the isolated perfused lung model. In vivo techniques like gamma scintigraphy, 3D SPECT, PET, MRI, fluorescence imaging and pharmacokinetic/pharmacodynamics analysis may be used for evaluation of aerosolized siRNA delivery systems. The use of inhalable siRNA delivery systems encounters barriers to their delivery, however overcoming the barriers while formulating a safe and effective delivery system will offer unique advances to the field of inhaled medicine.
Lung cancer is the leading cause of cancer deaths in both men and women in the United States accounting for about 27% of all cancer deceases. In our effort to develop newer therapy for lung cancer, we evaluated the combinatory antitumor effect of siRNA targeting VEGF and the PI3K/mTOR dual inhibitor PF-04691502. We analyzed the anticancer effect of siRNA VEGF and PF-04691502 combination on proliferation, colony formation and migration of A549 and H460 lung cancer cells. Additionally, we assessed the combination treatment antiangiogenic effect on human umbilical vein endothelial cells. Here, we show for the first time that the antiangiogenic siRNA VEGF potentiates the PF-04691502 anticancer activity against non–small-cell lung cancer. We observed a significant (P < 0.05) decrease in cell viability, colony formation, and migration for the combination comparing with the single drug treatment. We also showed a significant (P < 0.05) enhanced effect of the combination treatment inhibiting angiogenesis progression and tube formation organization compared to the single drug treatment groups. Our findings demonstrated an enhanced synergistic anticancer effect of siRNA VEGF and PF-04691502 combination therapy by targeting two main pathways involved in lung cancer cell survival and angiogenesis which will be useful for future preclinical studies and potentially for lung cancer patient management.
In this article, applications of engineered nanoparticles containing siRNA for inhalation delivery are reviewed and discussed. Diseases with identified protein malfunctions may be mitigated through the use of well-designed siRNA therapeutics. The inhalation route of administration provides local delivery of siRNA therapeutics to the lungs for various pulmonary diseases. A siRNA delivery system can be used to overcome the barriers of pulmonary delivery, such as anatomical barriers, mucociliary clearance, cough clearance, and alveolar macrophage clearance. Apart from naked siRNA aerosol delivery, previously studied siRNA carrier systems include those of lipidic, polymeric, peptide, or inorganic origin. These delivery systems can achieve pulmonary delivery through the generation of an aerosol via an inhaler or nebulizer. The preparation methodologies for these siRNA nanocarrier systems will be discussed herein. The use of inhalable nanocarrier siRNA delivery systems have barriers to their effective delivery, but overcoming these constraints while formulating a safe and effective delivery system will offer unique advances to the field of inhaled medicine.
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