Tsuruta James K, Sears Patrick R, Rebuli Meghan E, Weitz Andrew S, Durham Phillip G, Clapp Phillip W, Hill David B, Ostrowski Lawrence E, Dayton Paul A, Caughey Melissa C
Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC, 27599, USA.
Marsico Lung Institute, University of North Carolina, Chapel Hill, NC, USA.
Sci Rep. 2024 Dec 1;14(1):29840. doi: 10.1038/s41598-024-80933-x.
Impaired mucociliary transport is a distinguishing sign of cystic fibrosis, but current methods of evaluation are invasive or expose young patients to ionizing radiation. Contrast-enhanced ultrasound imaging may provide a feasible alternative. We formulated a cationic microbubble ultrasound contrast agent, to optimize adhesion to the respiratory mucus layer when inhaled. Potential toxicity was evaluated in human bronchial epithelial cell (hBEC) cultures following a 24-hour exposure, compared to positive and negative control conditions. In vivo tolerability and pulmonary image enhancement feasibility were evaluated in mice, comparing oropharyngeal administration of contrast agent to saline control. When induced to flow across mucus plated on microscope slides, cationic microbubbles demonstrated greater affinity for target samples than standard microbubbles. Cationic microbubbles elicited no proinflammatory or cytotoxic response in hBECs, nor were any cross-links to the cilia observed. Unlike standard microbubbles, cationic microbubbles mixed into the mucus layer, without epithelial absorption, and were observed to move with the mucus layer by the action of mucociliary transport. When administered to mice, cationic microbubbles enhanced sonographic visualization of the trachea, and were well-tolerated with no adverse effects. This developmental work supports the safety and feasibility of a mucus-targeting contrast agent that may be useful for pulmonary ultrasound applications.
黏液纤毛运输受损是囊性纤维化的一个显著特征，但目前的评估方法具有侵入性，或会使年轻患者暴露于电离辐射中。超声造影成像可能提供一种可行的替代方法。我们制备了一种阳离子微泡超声造影剂，以优化吸入时对呼吸道黏液层的黏附。在人支气管上皮细胞（hBEC）培养物中进行24小时暴露后，与阳性和阴性对照条件相比，评估了潜在毒性。在小鼠中评估了体内耐受性和肺部图像增强的可行性，将造影剂经口咽给药与生理盐水对照进行比较。当诱导阳离子微泡流过显微镜载玻片上的黏液时，与标准微泡相比，阳离子微泡对目标样本表现出更大的亲和力。阳离子微泡在hBECs中未引发促炎或细胞毒性反应，也未观察到与纤毛的任何交联。与标准微泡不同，阳离子微泡混入黏液层，未被上皮吸收，并观察到通过黏液纤毛运输作用随黏液层移动。当给小鼠给药时，阳离子微泡增强了气管的超声可视化，且耐受性良好，无不良反应。这项开发工作支持了一种靶向黏液的造影剂的安全性和可行性，该造影剂可能对肺部超声应用有用。
