Abstract
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.
Highlights
RNA interference (RNAi) is a process in which RNA molecules inhibit gene expression by causing the destruction of specific messenger RNA
Small interfering RNA are double stranded RNA molecules containing 20–25 nucleotides that are involved in the RNAi pathway and interfere with the expression of a specific gene with complementary nucleotide sequences (Agrawal N. et al, 2003)
In Part I, we review the modes of pulmonary delivery of Small interfering RNA (siRNA), the evaluation of aerosol drug delivery systems, and the rationale for the use of nanocarriers to overcome the barriers of pulmonary delivery and cellular uptake of siRNA
Summary
RNA interference (RNAi) is a process in which RNA molecules inhibit gene expression by causing the destruction of specific messenger RNA (mRNA). Youngren-Ortiz et al / KONA Powder and Particle Journal No 33 (2016) 63–85 of siRNA over small molecule drugs or protein therapeutics are that the sequences can be rapidly designed for highly specific inhibition of the target of interest and that the synthesis of siRNAs is relatively simple because it does not require a cellular expression system, complex protein purification, or refolding schemes Pulmonary diseases such as lung cancer, cystic fibrosis, pulmonary hypertension, asthma, and chronic obstructive pulmonary disorder (COPD) have potential siRNA therapeutic targets (Amarzguioui M. et al, 2005; Burnett J.C. and Rossi J.J., 2012; Kanasty R. et al, 2013). Part II focuses on the siRNA loaded non-viral particulates for aerosolized delivery systems, and preparation and characterization techniques for siRNA loaded nanoparticles
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