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

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

Although several in vivo studies demonstrated promising results of using RNAi therapeutics for the management of respiratory inflammatory diseases, there are several concerns that need to be taken into consideration with this approach. The distribution of naked siRNA following intranasal and intratracheal administration was investigated. It was shown that the siRNA molecules were predominantly accumulated in the peribronchial epithelial cells within 24 h post-administration [12] . Since the inflammatory mechanism of diseases like asthma appears to be driven by the activated T h 2 lymphocytes [218] , it is highly desirable for RNAi molecules to target the activated T cells in the airways to achieve therapeutic benefit. However, specific targeting to T cells is extremely difficult [174] . Effective T cells transfection in vitro was achieved by electroporation [219] , an approach that is not clinically feasible. Recently, a ligand-polymer conjugate siRNA delivery system, transferrin-polyethylenimine (Tf-PEI), has been developed to target T cells in the lungs [174] . The rational of such a design was based on the increased expression of transferrin receptors on T cells after activation. Biodistribution study showed that Tf-PEI polyplexes can selectively deliver the fluorescently labeled siRNA to the activated T cells in a murine asthma model. However, the therapeutic effect of the system was not evaluated. Therefore, targeting delivery of RNAi therapeutics to specific cell types associated with the disease is a field that certainly required further exploration.