Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Human respiratory tract is divided into the conducting region (nasal cavity, pharynx, trachea, bronchi and bronchioles) and the respiratory region (respiratory bronchioles and alveoli). The former is the pathway for gases conduction whereas the latter is the site of gaseous exchange [14] . The extensive branched structure of the airways with varying length and diameter presents the primary hurdle in pulmonary drug delivery. The mechanisms of inhaled particle deposition in the lungs include inertial impaction, gravitational sedimentation, diffusion, interception and electrostatic precipitation [33] . As illustrated in Figure 3 , the first three mechanisms are the major mechanisms which are greatly influenced by the aerodynamic size of the particles [34] . The optimal particle size for lung deposition is between 1 and 5 µm [35, 36] . Larger particles are likely to be impacted and trapped on the upper airway wall at bifurcations while the small particles from 0.1 to 1 µm are easily exhaled during normal breathing. Smaller particles under 100 nm may be successfully deposited in the alveolar space because of the increasing diffusional mobility [37] . However, aerosols under 100 nm are difficult to produce, which make their application less favorable. The presence of fluid layers in the airways, including the mucus and the pulmonary surfactant, also creates a barrier to the delivery of drug molecules to the lungs. Mucus is a gel of three-dimensional network structure. It acts as a sieve that filters out large molecules (>500 nm) [38] . Mucins, which are the major components of mucus, contain the hydrophilic glycosylated residues rich in serine and threonine and the hydrophobic non-glycosylated cysteine-rich domains. This characteristic allows electrostatic, hydrophilic and hydrophobic interactions between mucus and drug particles [39] . Since mucus is continuously produced, shed and replaced, and together with the mucociliary clearance action, the fast turnover rate of mucus leads to the rapid clearance of the entrapped drug molecules, preventing them from reaching the epithelium [40, 41] . Moreover, cough clearance that occurs when the mucus reaches the throat is another removal mechanism of RNAi molecules from the airways. On the other hand, the role of pulmonary surfactant in nucleic acid delivery is controversial. Pulmonary surfactant is composed of approximately 90% lipids and 10% proteins [42] . It has been suggested that the lipids and proteins in the lung surfactant interact with the non-viral cationic lipid-based delivery system, leading to the premature release of nucleic acids [43, 44] . Conversely, polymer-based delivery systems were found to be more compatible with pulmonary surfactant. Commercial pulmonary surfactant was employed in the preparation of some polymeric nanoparticles to facilitate the cellular uptake of siRNA to improve gene silencing effect [45, 46] .