Bahlool Ahmad Z, Cavanagh Brenton, Sullivan Andrew O', MacLoughlin Ronan, Keane Joseph, Sullivan Mary P O', Cryan Sally-Ann
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin 2, D02 YN77, Dublin, Ireland; Tissue Engineering Research Group, Royal College of Surgeons in Ireland (RCSI), 123 St Stephens Green, Dublin, Ireland; Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, The University of Dublin, Dublin 8, Ireland.
Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland RCSI, Dublin 2, Ireland.
Eur J Pharm Sci. 2024 May 1;196:106734. doi: 10.1016/j.ejps.2024.106734. Epub 2024 Feb 26.
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is second only to COVID-19 as the top infectious disease killer worldwide. Multi-drug resistant TB (MDR-TB) may arise because of poor patient adherence to medications due to lengthy treatment duration and side effects. Delivering novel host directed therapies (HDT), like all trans retinoic acid (ATRA) may help to improve drug regimens and reduce the incidence of MDR-TB. Local delivery of ATRA to the site of infection leads to higher bioavailability and reduced systemic side effects. ATRA is poorly soluble in water and has a short half-life in plasma. Therefore, it requires a formulation step before it can be administered in vivo. ATRA loaded PLGA nanoparticles suitable for nebulization were manufactured and optimized using a scalable nanomanufacturing microfluidics (MF) mixing approach (MF-ATRA-PLGA NPs). MF-ATRA-PLGA NPs demonstrated a dose dependent inhibition of Mtb growth in TB-infected A549 alveolar epithelial cell model while preserving cell viability. The MF-ATRA-PLGA NPs were nebulized with the Aerogen Solo vibrating mesh nebulizer, with aerosol droplet size characterized using laser diffraction and the estimated delivered dose was determined. The volume median diameter (VMD) of the MF-ATRA-PLGA NPs was 3.00 ± 0.18 μm. The inhaled dose delivered in adult and paediatric 3D printed head models under a simulated normal adult and paediatric breathing pattern was found to be 47.05 ± 3 % and 20.15 ± 3.46 % respectively. These aerosol characteristics of MF-ATRA-PLGA NPs supports its suitability for delivery to the lungs via inhalation. The data generated on the efficacy of an inhalable, scalable and regulatory friendly ATRA-PLGA NPs formulation provides a foundation on which further pre-clinical testing can be built. Overall, the results of this project are promising for future research into ATRA loaded NPs formulations as inhaled host directed therapies for TB.
由结核分枝杆菌（Mtb）引起的结核病是全球仅次于新冠病毒的第二大致命传染病杀手。由于治疗疗程长且有副作用，患者服药依从性差，可能会出现耐多药结核病（MDR-TB）。提供新型宿主导向疗法（HDT），如全反式维甲酸（ATRA），可能有助于改善药物治疗方案并降低耐多药结核病的发病率。将ATRA局部递送至感染部位可提高生物利用度并减少全身副作用。ATRA在水中溶解度低，在血浆中的半衰期短。因此，在体内给药之前需要进行制剂步骤。使用可扩展的纳米制造微流控（MF）混合方法（MF-ATRA-PLGA纳米颗粒）制造并优化了适合雾化的载有ATRA的聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒。在感染结核病的A549肺泡上皮细胞模型中，MF-ATRA-PLGA纳米颗粒表现出对Mtb生长的剂量依赖性抑制作用，同时保持细胞活力。使用Aerogen Solo振动网式雾化器对MF-ATRA-PLGA纳米颗粒进行雾化，用激光衍射表征气溶胶液滴大小，并确定估计的递送剂量。MF-ATRA-PLGA纳米颗粒的体积中值直径（VMD）为3.00±0.18μm。发现在模拟正常成人和儿童呼吸模式下，在成人和儿童3D打印头部模型中递送的吸入剂量分别为47.05±3%和20.15±3.46%。MF-ATRA-PLGA纳米颗粒的这些气溶胶特性支持其通过吸入递送至肺部的适用性。关于可吸入、可扩展且符合监管要求的ATRA-PLGA纳米颗粒制剂疗效的数据为进一步的临床前测试奠定了基础。总体而言，该项目的结果为未来研究载有ATRA的纳米颗粒制剂作为结核病吸入性宿主导向疗法带来了希望。
