Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware 19716, United States.
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States.
ACS Appl Mater Interfaces. 2020 Sep 2;12(35):38989-39004. doi: 10.1021/acsami.0c10900. Epub 2020 Aug 20.
Developing novel drug carriers for pulmonary delivery is necessary to achieve higher efficacy and consistency for treating pulmonary diseases while limiting off-target side effects that occur from alternative routes of administration. Metal-organic frameworks (MOFs) have recently emerged as a class of materials with characteristics well-suited for pulmonary drug delivery, with chemical tunability, high surface area, and pore size, which will allow for efficient loading of therapeutic cargo and deep lung penetration. UiO-66, a zirconium and terephthalic acid-based MOF, has displayed notable chemical and physical stability and potential biocompatibility; however, its feasibility for use as a pulmonary drug delivery vehicle has yet to be examined. Here, we evaluate the use of UiO-66 nanoparticles (NPs) as novel pulmonary drug delivery vehicles and assess the role of missing linker defects in their utility for this application. We determined that missing linker defects result in differences in NP aerodynamics but have minimal effects on the loading of model and therapeutic cargo, cargo release, biocompatibility, or biodistribution. This is a critical result, as it indicates the robust consistency of UiO-66, a critical feature for pulmonary drug delivery, which is plagued by inconsistent dosage because of variable properties. Not only that, but UiO-66 NPs also demonstrate pH-dependent stability, with resistance to degradation in extracellular conditions and breakdown in intracellular environments. Furthermore, the carriers exhibit high biocompatibility and low cytotoxicity in vitro and are well-tolerated in murine evaluations of orotracheally administered NPs. Following pulmonary delivery, UiO-66 NPs remain localized to the lungs before clearance over the course of seven days. Our results demonstrate the feasibility of using UiO-66 NPs as a novel platform for pulmonary drug delivery through their tunable NP properties, which allow for controlled aerodynamics and internalization-dependent cargo release while displaying remarkable pulmonary biocompatibility.
开发新型肺部给药药物载体对于提高治疗肺部疾病的疗效和一致性，同时限制替代给药途径引起的非靶向副作用是必要的。金属-有机框架（MOFs）作为一类材料，具有化学可调性、高表面积和孔径等特点，非常适合肺部药物输送，最近已经出现，能够有效地负载治疗性货物并深入肺部穿透。UiO-66 是一种基于锆和对苯二甲酸的 MOF，表现出显著的化学和物理稳定性和潜在的生物相容性；然而，其作为肺部药物输送载体的可行性尚未得到检验。在这里，我们评估了 UiO-66 纳米粒子（NPs）作为新型肺部药物输送载体的用途，并研究了缺失连接体缺陷在其应用中的作用。我们确定缺失连接体缺陷会导致 NPs 空气动力学特性的差异，但对模型和治疗性货物的负载、货物释放、生物相容性或生物分布的影响最小。这是一个关键的结果，因为它表明 UiO-66 的稳健一致性，这是肺部药物输送的一个关键特征，由于性质的变化，肺部药物输送一直受到剂量不一致的困扰。不仅如此，UiO-66 NPs 还表现出 pH 依赖性稳定性，在细胞外环境中具有抗降解性，在细胞内环境中则会发生分解。此外，该载体在体外表现出高生物相容性和低细胞毒性，并且在经口气管内给予 NPs 的小鼠评估中耐受性良好。肺部给药后，UiO-66 NPs 在七天的时间内仍会在肺部清除之前定位于肺部。我们的研究结果表明，UiO-66 NPs 可以作为一种新型肺部药物输送平台，通过其可调的 NP 特性来实现，这些特性可以控制空气动力学和与内化相关的货物释放，同时显示出显著的肺部生物相容性。
