Advanced Spray-Dried Inhalable Microparticles/Nanoparticles of an Innovative Mitophagy Activator for Targeted Lung Delivery: Design, Comprehensive Characterization, Human Lung Cell Culture, and In Vitro Aerosol Dispersion Performance.
Hasham Shafi, Andrea J Lora, Haley M Donow, Saurabh Aggarwal, Panfeng Fu, Ting Wang, Heidi M Mansour
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引用次数: 0
Abstract
Urolithin A (UA) has demonstrated the ability to stimulate mitophagy and enhance mitochondrial and cellular health in skeletal muscles in humans after oral administration. It is hypothesized that targeted delivery of UA as inhaled dry powders to the lungs will enhance mitochondrial health through mitochondrial biogenesis. This study aimed to engineer inhalable excipient-free powders of UA as dry powder inhalers (DPIs) for targeted pulmonary delivery. The particles were designed by particle engineering from dilute organic solutions of UA using the state-of-the-art spray drying technology in a closed mode. Comprehensive physicochemical characterization and advanced microscopy techniques were conducted to examine phase behavior, molecular properties, and particle properties, which are necessary for the rational design of advanced pulmonary inhalation aerosols. Molecular fingerprinting was conducted by using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and Raman spectroscopy. Chemical imaging and mapping were conducted using confocal Raman microscopy (CRM) and IR microscopy. The advanced spray-dried (SD) excipient-free powders were successfully produced at different spraying pump feed rates and exhibited favorable molecular and particle properties. The excipient-free SD powders exhibited outstanding in vitro aerosol dispersion performance with an FDI-approved human DPI device (Neohaler) and correlated with the spray drying pump rate. In vitro, cell viability of various human pulmonary cells from different lung regions demonstrated biocompatibility and safety at different doses of UA. The transepithelial electrical resistance (TEER) assay shows that UA maintains cell membrane integrity and barrier tightness, indicating its potential for safe and effective localized drug delivery without long-term adverse effects. These results demonstrated that UA has favorable physicochemical and in vitro properties for inhalation and can be successfully engineered into excipient-free inhalable microparticles/nanoparticles as DPIs.
尿石素 A（UA）已证明能够刺激有丝分裂，并在口服后增强人体骨骼肌中线粒体和细胞的健康。据推测，以吸入式干粉的形式向肺部定向输送尿囊素 A 将通过线粒体生物生成促进线粒体健康。本研究旨在设计可吸入的尿酸无辅料粉末，作为干粉吸入器（DPI）用于肺部靶向给药。这种颗粒是利用最先进的喷雾干燥技术，在封闭模式下从UA的稀释有机溶液中通过颗粒工程设计出来的。通过全面的物理化学表征和先进的显微镜技术，研究了相行为、分子特性和颗粒特性，这些都是合理设计先进的肺吸入气溶胶所必需的。利用衰减全反射-傅立叶变换红外（ATR-FTIR）光谱和拉曼光谱进行了分子指纹分析。使用共焦拉曼显微镜（CRM）和红外显微镜进行了化学成像和绘图。在不同的喷雾泵进料速率下，成功制备出了先进的不含辅料的喷雾干燥（SD）粉末，并表现出良好的分子和颗粒特性。不含辅料的SD粉末在体外气溶胶分散性能方面表现出色，可用于FDI批准的人体DPI设备（Neohaler），并与喷雾干燥泵速率相关。在体外，来自不同肺部区域的各种人类肺细胞的细胞存活率证明了不同剂量 UA 的生物相容性和安全性。经上皮细胞电阻（TEER）测定显示，UA 可保持细胞膜的完整性和屏障的紧密性，这表明它具有安全有效的局部给药潜力，且不会产生长期不良影响。这些结果表明，UA 具有良好的吸入理化和体外特性，可成功制成不含辅料的可吸入微颗粒/纳米颗粒作为 DPIs。
期刊介绍：
ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered.
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