Monosized Polymeric Microspheres Designed for Passive Lung Targeting: Biodistribution and Pharmacokinetics after Intravenous Administration
Monosized Polymeric Microspheres Designed for Passive Lung Targeting: Biodistribution and Pharmacokinetics after Intravenous Administration
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DOI：
10.1021/acsnano.9b09773
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发表时间：
2020-06-23
期刊：
影响因子：
17.1
通讯作者：
Hafeli, Urs O.
中科院分区：
文献类型：
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作者：
Agnoletti, Monica;Rodriguez-Rodriguez, Cristina;Hafeli, Urs O.
局部和全身治疗通常用于治疗细菌性肺部感染。使用肺靶向微球（MS）将抗生素递送至受感染肺组织的血管侧是常规给药途径的良好替代方案，允许局部高水平的抗生素。这种输送途径也可以补充吸入抗生素治疗，特别是在肺功能受损的情况下。我们使用流动聚焦玻璃微流控芯片制备并表征了负载左氧氟沙星的单分散聚乳酸-羟基乙酸共聚物（PLGA）微球。体外实验表明，包封的LVX在5天内表现出双相控释，并保留了其抗菌活性。MS降解进行了研究，在体外通过横截面的MS使用聚焦离子束扫描电子显微镜和在体内通过组织学检查的肺组织从小鼠静脉注射MS。MS的表面形态和内部基质的变化，而在体内的降解速度比在体外快3倍。未观察到对内皮细胞和肺上皮细胞活力或溶血活性的影响。为了评价MS的药代动力学和生物分布，在体内用单光子发射计算机断层扫描成像对（111）铟标记的PLGA MS进行了10天的完整定量成像。PLGA微球在肺毛细血管内分布均匀。总体而言，静脉内施用12 μ m PLGA MS适用于被动肺靶向和肺部治疗。
Local as well as systemic therapy is often used to treat bacterial lung infections. Delivery of antibiotics to the vascular side of infected lung tissue using lung-targeting microspheres (MS) is a good alternative to conventional administration routes, allowing for localized high levels of antibiotics. This delivery route can also complement inhaled antibiotic therapy, especially in the case of compromised lung function. We prepared and characterized monodisperse poly(lactic-co-glycolic acid) (PLGA) MS loaded with levofloxacin using a flow-focusing glass microfluidic chip. In vitro characterization showed that the encapsulated LVX displayed a biphasic controlled release during 5 days and preserved its antibacterial activity. The MS degradation was investigated in vitro by cross-sectioning the MS using a focused ion beam scanning electron microscope and in vivo by histological examination of lung tissue from mice intravenously administered with the MS. The MS showed changes in the surface morphology and internal matrix, whereas the degradation in vivo was 3 times faster than that in vitro. No effect on the viability of endothelial and lung epithelial cells or hemolytic activity was observed. To evaluate the pharmacokinetics and biodistribution of the MS, complete quantitative imaging of the (111)indium-labeled PLGA MS was performed in vivo with single-photon emission computed tomography imaging over 10 days. The PLGA MS distributed homogeneously in the lung capillaries. Overall, intravenous administration of 12 mu m PLGA MS is suitable for passive lung targeting and pulmonary therapy.