Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.
Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.
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DOI：
10.1002/anbr.202200106
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发表时间：
2023-03
影响因子：
3.4
通讯作者：
Brenner, Jacob S
中科院分区：
文献类型：
--
作者：
Ferguson, Laura T;Ma, Xiaonan;Myerson, Jacob W;Wu, Jichuan;Glassman, Patrick M;Zamora, Marco E;Hood, Elizabeth D;Zaleski, Michael;Shen, Mengwen;Essien, Eno-Obong;Shuvaev, Vladimir V;Brenner, Jacob S
肺泡疾病，如肺纤维化，是发病率和死亡率的主要原因，但针对它们开发的药物非常少。这种差距的一个主要原因是，吸入后，药物迅速远离肺泡，由于他们的高灌注。为了解决这一问题，研究了纳米级药物载体使用含有尼达尼布（一种用于肺纤维化的抗纤维化药物）的可吸入脂质体制剂显著改善肺药代动力学的机制。与口服尼达尼布相比，在小鼠肺中直接滴注脂质体可使尼达尼布的总肺递送量增加8000倍，肺半衰期增加10倍。与直觉相反的是，肺表面活性物质既不溶解也不聚集脂质体。相反，每个肺室（肺泡液，肺泡白细胞和实质）洗脱脂质体超过24小时，可能作为“药物仓库”。在表面活性剂层中沉积后，脂质体以不饱和的方式在3-6小时内转移到肺泡白细胞（其占滴注的总肺剂量的令人惊讶的小1-5%）。此外，肺实质的所有细胞层都吸收脂质体。本文阐明的这些和其他机制应该指导未来用于肺泡疾病的吸入纳米药物的工程。吸入载药脂质体到达远端肺，在那里它们与肺泡液、白细胞和实质细胞相互作用。脂质体在支气管肺泡灌洗液中不会溶解或聚集，肺泡巨噬细胞也不会饱和。与口服给药相比，这些经气管内滴注的脂质体向肺递送的货物药物多8000倍，同时肺半衰期增加10倍。
Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano‐scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000‐fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as “drug depots.” After deposition in the surfactant layer, liposomes are transferred over 3–6 h to alveolar leukocytes (which take up a surprisingly minor 1–5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases. Inhaled drug‐loaded liposomes reach the distal lung where they interact with alveolar fluid, leukocytes, and parenchymal cells. The liposomes are not lysed or aggregated in bronchoalveolar lavage fluid, and alveolar macrophages are not saturable. Compared to oral dosing, these intratracheally instilled liposomes deliver 8000‐fold more cargo drug to the lung with a concomitant tenfold increase in lung half life.