Chow Michael Y T, Qiu Yingshan, Lo Fiona F K, Lin Hinson H S, Chan Hak-Kim, Kwok Philip C L, Lam Jenny K W
Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
Advanced Drug Delivery Group, Faculty of Pharmacy, Building A15, The University of Sydney, Sydney, NSW 2006, Australia.
Int J Pharm. 2017 Sep 15;530(1-2):40-52. doi: 10.1016/j.ijpharm.2017.07.013. Epub 2017 Jul 15.
Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC).
通过RNA干扰进行基因沉默来治疗各种呼吸系统疾病，短干扰RNA（siRNA）的肺部给药已在动物和临床研究中得到广泛研究。其中一些研究表明，施用裸siRNA（不使用任何递送载体）可实现令人满意的基因沉默效果，这是肺部给药的一个独特特征。液体气溶胶大多被使用，而关于将粉末气溶胶用于siRNA的研究非常有限。在本研究中，siRNA与甘露醇和L-亮氨酸共同喷雾干燥，后者是一种分散增强剂。据我们所知，这是首次使用喷雾干燥技术将裸siRNA制剂制成可吸入干粉。使用下一代撞击器（NGI）评估该粉末的气溶胶性能。制剂中L-亮氨酸的存在可改善含siRNA粉末的雾化。X射线光电子能谱（XPS）结果表明，L-亮氨酸在颗粒表面富集并促进粉末分散。在所研究的不同siRNA制剂中，含有50%w/w L-亮氨酸的制剂表现出最佳的空气动力学性能，具有约80%的高发射分数（EF）和45%的适度细颗粒分数（FPF）。重要的是，通过凝胶阻滞试验和高效液相色谱（HPLC）评估，siRNA的完整性成功得以保留。
