Selective targeting of alveolar type II respiratory epithelial cells by anti-surfactant protein-C antibody-conjugated lipoplexes.
Selective targeting of alveolar type II respiratory epithelial cells by anti-surfactant protein-C antibody-conjugated lipoplexes.
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DOI：
10.1016/j.jconrel.2015.02.016
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发表时间：
2015-04-10
期刊：
影响因子：
--
通讯作者：
Davis IC
中科院分区：
文献类型：
--
作者：
Wu Y;Ma J;Woods PS;Chesarino NM;Liu C;Lee LJ;Nana-Sinkam SP;Davis IC
Ⅱ型肺泡（ATII）呼吸上皮细胞对正常肺功能至关重要。它们可能在急性肺损伤、肺纤维化和肺腺癌等疾病的发病机制中也起着核心作用。因此，ATII细胞是重要的治疗靶点。然而，体内有效的ATII细胞特异性药物递送需要合适大小的载体，这些载体能够穿过覆盖在ATII细胞上的疏水性肺泡表面活性物质膜和极性水层，并且在被摄取时不会引起ATII细胞功能障碍、肺部炎症、肺损伤或过度的全身扩散和副作用。我们已经开发了脂质复合物作为一种通用的纳米颗粒载体系统用于药物/RNA递送。为了优化它们在肺部的定位和ATII细胞特异性，将脂质复合物与一种针对ATII细胞特异性抗原表面活性蛋白 - C（SP - C）的抗体结合，然后通过鼻腔给予C57BL/6小鼠。经鼻腔给予的抗 - SP - C结合的脂质复合物在体内对小鼠ATII细胞的靶向特异性>70%，在ATII细胞内保留至少48小时，并且在其他肺细胞类型或内脏中没有显著积累。在用含有测试微小RNA miR - 486的抗 - SP - C结合的脂质复合物治疗48小时后，通过实时定量聚合酶链反应（qRT - PCR）检测，成熟miR - 486在ATII细胞中的表达比全肺高约4倍，并且在其他内脏中未检测到。在6天的时间内，脂质复合物没有引起体重减轻、低氧血症、肺功能障碍、肺水肿或肺部炎症。这些发现表明，靶向ATII细胞的脂质复合物展现出了一种有效的药物递送系统的所有期望特性，可用于治疗主要由ATII细胞功能障碍导致的肺部疾病。
Alveolar type II (ATII) respiratory epithelial cells are essential to normal lung function. They may be also central to the pathogenesis of diseases such as acute lung injury, pulmonary fibrosis, and pulmonary adenocarcinoma. Hence, ATII cells are important therapeutic targets. However, effective ATII cell-specific drug delivery in vivo requires carriers of an appropriate size, which can cross the hydrophobic alveolar surfactant film and polar aqueous layer overlying ATII cells, and be taken up without inducing ATII cell dysfunction, pulmonary inflammation, lung damage, or excessive systemic spread and side-effects. We have developed lipoplexes as a versatile nanoparticle carrier system for drug/RNA delivery. To optimize their pulmonary localization and ATII cell specificity, lipoplexes were conjugated to an antibody directed against the ATII cell-specific antigen surfactant protein-C (SP-C) then administered to C57BL/6 mice via the nares. Intranasally-administered, anti-SP-C-conjugated lipoplexes targeted mouse ATII cells with >70% specificity in vivo, were retained within ATII cells for at least 48 hours, and did not accumulate at significant levels in other lung cell types or viscera. 48 hours after treatment with anti-SP-C-conjugated lipoplexes containing the test microRNA miR-486, expression of mature miR-486 was approximately 4-fold higher in ATII cells than whole lung by qRT-PCR, and was undetectable in other viscera. Lipoplexes induced no weight loss, hypoxemia, lung dysfunction, pulmonary edema, or pulmonary inflammation over a 6-day period. These findings indicate that ATII cell-targeted lipoplexes exhibit all the desired characteristics of an effective drug delivery system for treatment of pulmonary diseases that result primarily from ATII cell dysfunction.
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作者：
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DOI：
10.1152/ajplung.00458.2006
发表时间：
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