期刊
JOURNAL OF CONTROLLED RELEASE
卷 187, 期 -, 页码 91-100出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2014.05.021
关键词
Polyethylene glycol; Proteins; Pulmonary drug delivery; Mucoadhesion
资金
- WALEO3 program of the Walloon Region, Belgium [816862]
- Fonds Speciaux de la Recherche (University of Liege) [C-14/109]
- Interuniversity Attraction Poles Program-Belgian Science Policy/Inter-University Network for Fundamental Research Program (Brussels, Belgium) [6/35, 7/30]
Inhalation aerosols offer a targeted therapy for respiratory diseases. However, the therapeutic efficacy of inhaled biopharmaceuticals is limited by the rapid clearance of macromolecules in the lungs. The aim of this research was to study the effects of the PEGylation of antibody fragments on their local residence time after administration to the respiratory tract. We demonstrate that the conjugation of a two-armed 40-kDa polyethylene glycol (PEG) chain to anti-interleukin-17A (IL-17A) F(ab')(2) and anti-IL-13 Fab' greatly prolonged the presence of these fragments within the lungs of mice. The content of PEGylated antibody fragments within the lungs plateaued up to 4 h post-delivery, whereas the clearance of unconjugated proteins started immediately after administration. Forty-eight hours post-delivery, F(ab')(2) and Fab' contents in the lungs had decreased to 10 and 14% of the dose initially deposited, respectively. However, this value was 40% for both PEG40-F(ab')(2) and PEG40-Fab'. The prolonged pulmonary residency of the anti-IL-17A PEG40-F(ab')(2) translated into an improved efficacy in reducing lung inflammation in a murine model of house dust mite-induced lung inflammation. We demonstrate that PEGylated proteins were principally retained within the lung lumen rather than the nasal cavities or lung parenchyma. In addition, we report that PEG increased pulmonary retention of antibody fragments through mucoadhesion and escape from alveolar macrophages rather than increased hydrodynamic size or improved enzymatic stability. The PEGylation of proteins might find broad application in the local delivery of therapeutic proteins to diseased airways. (C) 2014 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据