Myers M A, Thomas D A, Straub L, Soucy D W, Niven R W, Kaltenbach M, Hood C I, Schreier H, Gonzalez-Rothi R J
Pulmonary Division, College of Medicine, University of Florida, Gainesville 32610.
Exp Lung Res. 1993 Jan-Mar;19(1):1-19. doi: 10.3109/01902149309071077.
Administering liposome-encapsulated drugs by aerosols could be a feasible way of targeting drugs to the lung, specifically to pulmonary alveolar macrophages (AM). In the mouse model, we characterized uptake of carboxyfluorescein- (CF-) labeled liposomes by AM in vivo after acute inhalation of liposome aerosols, and the effects of chronic exposure to liposome aerosols on lung histology and AM function. Mice were placed in a nose-only exposure module and exposed to liposome or saline aerosols for 1 h per day, 5 days per week, for 4 weeks. Five mice of both the experimental and control groups were removed weekly and their lungs examined. Liposomes were made from hydrogenated soy phosphatidylcholine (HSPC) at 50 mg/mL. In vivo uptake of liposomes by AM was documented by fluorescence microscopy and flow cytometry of bronchoalveolar lavage (BAL). A consistent amount of 1-3 micrograms of lipid inhaled per dosing per mouse was estimated from fluorescence measurements. Addition of Triton X-100 to BAL caused a significant increase in fluorescence intensity, indicating that liposomes remained intact in the lung for a period of time. The chronic inhalation study showed no histologic changes of the lung or untoward effects on the general health or survival of animals. AM phagocytic function, intracellular killing, and fatty acid composition were not affected. Transmission electron microscopy and morphometry (computerized image analysis) of AM likewise showed no alterations as a result of the treatment. It was concluded that AM uptake of liposomes delivered by aerosol was operant in vivo. This finding validates the concept of alveolar macrophage-directed delivery of liposome-encapsulated agents to the lung via inhalation. It was also concluded that chronic liposome aerosol inhalation in mice produced no untoward effects on survival, histopathology, and macrophage function. These data confirm and extend prior findings regarding the functional and morphologic interactions of liposomes with AM in vitro (Gonzalez-Rothi et al., Exp. Lung Res. 17:687-705, 1991).
通过气雾剂给药脂质体包裹的药物可能是将药物靶向肺部，特别是肺泡巨噬细胞（AM）的一种可行方法。在小鼠模型中，我们对急性吸入脂质体气雾剂后体内AM对羧基荧光素（CF）标记脂质体的摄取情况，以及长期暴露于脂质体气雾剂对肺组织学和AM功能的影响进行了表征。将小鼠置于仅通过鼻腔暴露的模块中，每周5天，每天暴露于脂质体或盐雾气溶胶1小时，持续4周。每周从实验组和对照组中各取出5只小鼠，检查其肺部。脂质体由50 mg/mL的氢化大豆磷脂酰胆碱（HSPC）制成。通过荧光显微镜和支气管肺泡灌洗（BAL）的流式细胞术记录体内AM对脂质体的摄取情况。根据荧光测量估计，每只小鼠每次给药吸入的脂质一致量为1 - 3微克。向BAL中添加 Triton X - 100导致荧光强度显著增加，表明脂质体在肺中保持完整一段时间。长期吸入研究显示肺没有组织学变化，对动物的总体健康或生存也没有不良影响。AM的吞噬功能、细胞内杀伤和脂肪酸组成均未受影响。AM的透射电子显微镜检查和形态计量学（计算机图像分析）同样显示治疗后没有改变。得出的结论是，气雾剂递送的脂质体在体内可被AM摄取。这一发现验证了通过吸入将脂质体包裹的药物定向递送至肺泡巨噬细胞到肺的概念。还得出结论，小鼠长期吸入脂质体气雾剂对生存、组织病理学和巨噬细胞功能没有不良影响。这些数据证实并扩展了先前关于脂质体与AM在体外功能和形态相互作用的研究结果（Gonzalez - Rothi等人，《实验肺研究》17:687 - 705，1991）。
