Inhibition of Human Neutrophil Elastase by α1-Antitrypsin Functionalized Colloidal Microcarriers
Inhibition of Human Neutrophil Elastase by α1-Antitrypsin Functionalized Colloidal Microcarriers
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DOI：
10.1021/nn301791w
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发表时间：
2012-07-01
期刊：
影响因子：
17.1
通讯作者：
Lessig, Jacqueline
中科院分区：
文献类型：
--
作者：
Reibetanz, Uta;Schoenberg, Maria;Lessig, Jacqueline
层层包覆(LBL)的微载体为活性物质进入特定细胞和组织提供了很好的运输系统。相反电荷聚电解质的组装使得载体的模块化结构成为可能，从而优化了药物分子的集成和应用。在这里，我们报告了胶体微载体对α(1)-抗胰蛋白酶(AT)的多层掺入和转运。AT是一种抗炎药，对其前炎性拮抗剂人中性粒细胞弹性蛋白酶(HNE)具有抑制作用。高蛋白水解酶HNE在炎症过程中由多形核白细胞(PMN)释放，可导致宿主组织破坏和疼痛。这项研究的高潜力是基于AT功能化LW在细胞内和细胞外的同时应用。承运人。载体作用于PMN后，在21h内对HNE有明显的抑制作用。PMN吞噬的微载体在吞噬溶酶体内随时间的变化而降解，从而使AT逐步释放。在这里，AT在释放之前使HNE失活，这避免了细胞外空间HNE浓度的进一步增加，从而降低了进一步组织破坏的风险。此外，AT表面功能化的微载体可以抑制细胞外空间已经释放的HNE。最后，这项研究证明了LBL载体成功地用于同时抑制细胞外和细胞内的HNE，目的是重新平衡蛋白酶和抗蛋白酶的浓度，并随后终止慢性炎症。
Layer-by-layer (LbL)-coated microcarriers offer a good opportunity as transport systems for active agents into specific cells and tissues. The assembling of oppositely charged polyelectrolytes enables a modular construction of the carriers and therefore an optimized integration and application of drug molecules. Here, we report the multilayer incorporation and transport of alpha(1)-antitrypsin (AT) by colloidal microcarriers. AT is an anti-inflammatory agent and shows inhibitory effects toward its pro-inflammatory antagonist, human neutrophil elastase (HNE). The highly proteolytic enzyme HNE is released by polymorphonuclear leukocytes (PMNs) during inflammatory processes and can cause host tissue destruction and pain. The high potential of this study is based on a simultaneous intra- and extracellular application of AT-functionalized LW. carriers. Carrier application in PMNs results in significant HNE inhibition within 21 h. Microcarriers phagocytosed by PMNs were time dependently decomposed inside phagolysosomes, which enables the step-by-step release of AT. Here, AT inactivates HNE before being released, which avoids a further HNE concentration increase in the extracellular space and, subsequently, reduces the risk of further tissue destruction. Additionally, AT surface-functionalized microcarriers allow the inhibition of already released HNE in the extracellular space. Finally, this study demonstrates the successful application of LbL carriers for a concurrent extra- and intracellular HNE inhibition aiming the rebalancing of protease and antiprotease concentrations and the subsequent termination of chronic inflammations.