Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers.
Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers.
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即使存在预先存在的脂质单层，雾化脂质分散体也能实现抗生素在肺气道表面模拟物的运输。
DOI：
10.1089/jamp.2017.1412
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发表时间：
2018
影响因子：
3.4
通讯作者：
Tilton,RobertD
中科院分区：
文献类型：
--
作者：
Iasella,StevenV;Stetten,AmyZ;Corcoran,TimothyE;Garoff,Stephen;Przybycien,ToddM;Tilton,RobertD
背景：继发性肺部感染是囊性纤维化肺病相关发病的主要原因。雾化抗生素吸入具有潜在的优势，但由于气道空气动力学和沉积模式的改变限制了药物进入感染区域，因此效果有限。更好地到达感染区域的一种潜在策略是用表面活性剂配制气雾剂，诱导表面张力梯度并通过沿气道表面液体 (ASL) 的马兰戈尼运输驱动沉积后药物扩散。由于这依赖于表面活性剂诱导的表面张力降低，内源性脂质单层的存在可能会阻碍药物分散性能。方法：用二棕榈酰磷脂酰胆碱（DPPC）（内源性肺表面活性剂的主要成分）配制妥布霉素溶液，以驱动沉积后气溶胶在模型 ASL 上的扩散，该模型基于预沉积 DPPC 的猪胃粘蛋白（PGM）水溶液的液层或“亚相”从气溶胶沉积区以外的区域收集体外亚相样品，并使用封闭酶供体免疫测定法测定妥布霉素浓度。跟踪珠穿过面下相表面的运动以及气溶胶沉积时表面张力的相应降低均在有和没有预沉积 DPPC 单层的情况下进行跟踪。测量 DPPC 在 PGM 溶液亚相上的表面张力/面积等温线，以帮助解释妥布霉素的分散行为。 结果和结论：无论是否存在预先沉积的脂质，在用 DPPC 配制的气溶胶中，妥布霉素都会从沉积区域迁移出去，并且在两种情况下，在生物学相关的长度尺度 (∼8 cm) 上，妥布霉素浓度相似。当 DPPC 从气溶胶中沉积时，它会产生超低表面张力 (<5 mN/m)，即使存在致密的 DPPC 背景层，也会驱动 Marangoni 流动。因此，雾化磷脂，例如 DPPC，可能是人肺中的有效扩散剂。
Background:Secondary lung infections are the primary cause of morbidity associated with cystic fibrosis lung disease. Aerosolized antibiotic inhalation is potentially advantageous but has limited effectiveness due to altered airway aerodynamics and deposition patterns that limit drug access to infected regions. One potential strategy to better reach infected areas is to formulate aerosols with surfactants that induce surface tension gradients and drive postdeposition drug dispersal via Marangoni transport along the airway surface liquid (ASL). Since this relies on surfactant-induced surface tension reduction, the presence of endogenous lipid monolayers may hinder drug dispersal performance.Methods:Tobramycin solutions were formulated with dipalmitoylphosphatidylcholine (DPPC), a major component of endogenous pulmonary surfactant, to drive postdeposition aerosol dispersal across a model ASL based on a liquid layer or “subphase” of aqueous porcine gastric mucin (PGM) solution with predeposited DPPC monolayers to mimic the endogenous surfactant.In vitrosubphase samples were collected from regions outside the aerosol deposition zone and assayed for tobramycin concentration using a closed enzyme donor immunoassay. The motion of a tracking bead across the subphase surface and the corresponding decrease in surface tension on aerosol deposition were tracked both with and without a predeposited DPPC monolayer. The surface tension/area isotherm for DPPC on PGM solution subphase was measured to aid in the interpretation of the tobramycin dispersal behavior.Results and Conclusions:Transport of tobramycin away from the deposition region occurs in aerosols formulated with DPPC whether or not predeposited lipid is present, and tobramycin concentrations are similar in both cases across biologically relevant length scales (∼8 cm). When DPPC is deposited from an aerosol, it induces ultralow surface tensions (<5 mN/m), which drive Marangoni flows, even in the presence of a dense background layer of DPPC. Therefore, aerosolized phospholipids, such as DPPC, will likely be effective spreading agents in the human lung.