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BARRIERS TO siRNA DELIVERY TO THE LUNG

As illustrated in Figure 3.1, there are generally five steps that siRNA go through when administered via pulmonary route. Although local delivery of siRNA could obviate the need for targeting and the interaction with serum nuclease to minimize degradation, the lung itself possesses some intrinsic anatomic, physiologic, immunologic, and metabolic hurdles for efficient siRNA delivery. The specific barriers to lung

Schematic illustrates steps involved in the delivery of siRNA into the lungs

FIGURE 3.1 Schematic illustrates steps involved in the delivery of siRNA into the lungs. (Reproduced from Lam, J.K.-W. et al., Adv. Drug Deliv. Rev., 64(1), 1, 2012. With permission.) administration include highly branched anatomic structure ranging from the trachea to the alveoli, phagocytosis by macrophages, and the presence of mucus on the surface of conducting airway, which could effectively capture and remove the inhaled foreign particles by the beating of the cilia and mucociliary clearance. In addition, depending on the region of deposition, siRNA might be absorbed into the systemic circulation, which would adversely decrease local concentration, decrease therapeutic effect, and raise potential side effects.10

It was well known that the size, density, shape, and surface of the particle in which the siRNA is formulated and the patient’s pulmonary function are two main factors determining the fate of siRNA-incorporated particle in lung.11 Carefully screening and optimizing the aerosolization properties of the formulation could facilitate the overcoming of the lung-specific barriers mentioned earlier to ensure siRNA reaches its target site in the lung (the first two steps shown in Figure 3.1). But the remaining processes of entering the target cell, escaping from endosome, and being released from the delivery agent are still needed to go through before siRNA starts to trigger the RNAi pathway.

 
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