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作者： Yun Wua, b, Junyu Ma b,  Parker S. Woodsc,  Nicholas M. Chesarinod, Chang Liua,  L. James Leeb, e , Serge P. Nana-Sinkamf, Ian C. Davisc

a Dept. of Biomedical Engineering, State University of New York at Buffalo, Bonner Hall, Buffalo, NY 14260, USA

b Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Smith Laboratory, 174W. 18th Ave., Columbus, OH 43210, USA

c Dept. of Veterinary Biosciences, The Ohio State University, Goss Laboratories, 1925 Coffey Road, Columbus, OH 43210, USA

d Dept. of Microbial Infection & Immunity, The Ohio State University, Biomedical Research Tower, 460W. 12th Ave., Columbus, OH 43210, USA

e William G. Lowrie Dept. of Chemical and Biomolecular Engineering, The Ohio State University, Koffolt Laboratories, 140W. 19th Ave., Columbus, OH 43210, USA

f Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Davis Heart and Lung Research Institute, 473W. 12th Ave., Columbus, OH 43210, USA

 

摘要：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 h, and did not accumulate at significant levels in other lung cell types or viscera. 48 h after treatment with anti-SP-C-conjugated lipoplexes containing the test microRNA miR-486, expression of mature miR-486 was approximay 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 the treatment of pulmonary diseases that result primarily from ATII cell dysfunction.

 

關鍵詞：Lipoplex; Alveolar type II cell; Surfactant protein-C; MicroRNA; Targeted delivery