Nektar Therapeutics, 201 Industrial Road, San Carlos, California 94070, USA.
J Pharm Sci. 2009 Aug;98(8):2847-56. doi: 10.1002/jps.21635.
Polyethylene glycol (PEG) polymers are large amphiphilic molecules that are highly hydrated in solution. To explore the permeability properties of different sized PEG polymers across epithelial membranes in vivo, we examined the absorption of fluorescently labeled PEG conjugates sized 0.55-20 kDa from the lung, since this system provides a reservoir that limits rapid diffusion of molecules away from the site of delivery and enables permeability over longer times to be examined. Following intratracheal delivery in rats, the PEG polymers underwent absorption with first-order kinetics described by single exponential decay curves. PEG size produced a marked influence on the rate of uptake from the lung, with half-lives ranging from 2.4 to 13 h, although above a size of 5 kDa, no further change in rate was observed. PEG size likewise affected retention in alveolar macrophages and in lung tissue; whereas smaller PEG sizes (<2 kDa) were effectively cleared within 48 h, larger PEG sizes (>5 kDa) remained in lung cells and tissue for up to 7 days. These data demonstrate that PEG polymers can be absorbed across epithelial membranes and that PEG size plays a dominant role in controlling the rate and mechanism of absorption.
聚乙二醇（PEG）聚合物是大型两亲分子，在溶液中高度水合。为了研究不同大小的 PEG 聚合物在体内穿过上皮细胞膜的渗透性，我们研究了从肺部吸收的荧光标记的 PEG 缀合物，大小为 0.55-20 kDa，因为该系统提供了一个储库，限制了分子从给药部位快速扩散，并能够在更长的时间内检查渗透性。在大鼠气管内给药后，PEG 聚合物以单指数衰减曲线描述的一级动力学吸收。PEG 大小对肺吸收率有显著影响，半衰期范围为 2.4 至 13 小时，但大于 5 kDa 时，吸收率不再变化。PEG 大小同样影响肺泡巨噬细胞和肺组织中的保留；较小的 PEG 大小（<2 kDa）在 48 小时内有效清除，而较大的 PEG 大小（>5 kDa）在肺细胞和组织中保留长达 7 天。这些数据表明，PEG 聚合物可以穿过上皮细胞膜吸收，PEG 大小在控制吸收的速率和机制方面起着主导作用。
