Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, MD, USA.
Nanomedicine (Lond). 2011 Feb;6(2):365-75. doi: 10.2217/nnm.10.123.
Sputum poses a critical diffusional barrier that strongly limits the efficacy of drug and gene carriers in the airways of individuals with cystic fibrosis (CF). Previous attempts to enhance particle penetration of CF sputum have focused on either reducing its barrier properties via mucolytics, or decreasing particle adhesion to sputum constituents by coating the particle surface with non-mucoadhesive polymers, including polyethylene glycol (PEG). Neither approach has enabled particles to penetrate expectorated sputum at rates previously observed for non-mucoadhesive nanoparticles in human cervicovaginal mucus. Here, we sought to investigate whether a common mucolytic, N-acetyl cysteine (NAC), in combination with dense PEG coatings on particles, can synergistically enhance particle penetration across fresh undiluted CF sputum.
MATERIALS & METHODS: We used high-resolution multiple particle tracking to measure the diffusion of uncoated and PEG-coated nanoparticles in native and NAC-treated CF sputum.
We discovered that 200 nm particles, if densely coated with PEG, were able to penetrate CF sputum pretreated with NAC with average speeds approaching their theoretical speeds in water. Based on the rapid penetration of PEG-coated particles in NAC-treated sputum, we determined that the average spacing between sputum mesh elements was increased from 145 ± 50 nm to 230 ± 50 nm upon NAC treatment. Mathematical models based on particle transport rates suggest as much as 75 and 30% of 200 and 500 nm PEG-coated particles, respectively, may penetrate a physiologically thick NAC-treated CF sputum layer within 20 min. Uncoated particles were trapped in CF sputum pretreated with NAC nearly to the same extent as in native sputum, suggesting that NAC treatment alone offered little improvement to particle penetration.
NAC facilitated rapid diffusion of PEG-coated, muco-inert nanoparticles in CF sputum. Our results provide a promising strategy to improve drug and gene carrier penetration in CF sputum, offering hope for improved therapies for CF.
痰液是一个严重的扩散屏障，强烈限制了药物和基因载体在囊性纤维化（CF）患者气道中的疗效。先前为了增强粒子穿透 CF 痰液的能力，尝试通过黏液溶解剂降低其屏障特性，或通过用非黏液附着聚合物（包括聚乙二醇（PEG））涂覆粒子表面，减少粒子与痰液成分的黏附。这两种方法都不能使粒子以以前在人宫颈阴道黏液中观察到的非黏液附着纳米粒子的速度穿透咳出的痰液。在这里，我们试图研究常见的黏液溶解剂 N-乙酰半胱氨酸（NAC）与粒子上的密集 PEG 涂层的组合是否可以协同增强粒子穿过新鲜未稀释 CF 痰液的穿透率。
我们使用高分辨率多粒子跟踪测量未涂层和 PEG 涂层纳米粒子在天然和 NAC 处理的 CF 痰液中的扩散。
我们发现，如果致密地涂覆 200nm 粒子的 PEG，则能够以接近其在水中的理论速度的平均速度穿透用 NAC 预处理的 CF 痰液。基于 PEG 涂层粒子在 NAC 处理的痰液中的快速穿透，我们确定在用 NAC 处理后，痰液网元之间的平均间距从 145 ± 50nm 增加到 230 ± 50nm。基于粒子传输速率的数学模型表明，多达 75%和 30%的 200nm 和 500nm PEG 涂层粒子可能在 20min 内穿透生理厚度的 NAC 处理的 CF 痰液层。未涂层的粒子在用 NAC 预处理的 CF 痰液中几乎与在天然痰液中一样被截留，这表明单独用 NAC 处理对粒子穿透的改善很小。
NAC 促进了 PEG 涂层、黏液惰性纳米粒子在 CF 痰液中的快速扩散。我们的结果为改善 CF 痰液中的药物和基因载体穿透率提供了一个有前途的策略，为 CF 的治疗提供了新的希望。
