Anti-PEG antibodies alter the mobility and biodistribution of densely PEGylated nanoparticles in mucus.
Anti-PEG antibodies alter the mobility and biodistribution of densely PEGylated nanoparticles in mucus.
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DOI：
10.1016/j.actbio.2016.07.019
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发表时间：
2016-10-01
影响因子：
9.7
通讯作者：
Lai SK
中科院分区：
文献类型：
--
作者：
Henry CE;Wang YY;Yang Q;Hoang T;Chattopadhyay S;Hoen T;Ensign LM;Nunn KL;Schroeder H;McCallen J;Moench T;Cone R;Roffler SR;Lai SK
特异性结合聚乙二醇(PEG)的抗体可以导致聚乙二醇化治疗药物从体循环中迅速消除。我们最近发现，病毒结合的免疫球蛋白可以通过免疫球蛋白和粘蛋白之间的多个低亲和力交联剂将病毒固定在粘液中。然而，目前尚不清楚粘液中的抗聚乙二醇化抗体是否也会改变聚乙二醇化纳米颗粒的渗透，从而改变其在粘膜表面的生物分布。我们发现，抗聚乙二醇IgG和免疫球蛋白M都可以很容易地结合紧密包裹着聚乙二醇聚合物的纳米颗粒，以最大限度地减少与粘液成分的粘附性相互作用。在小鼠宫颈阴道粘液中加入抗-PEGI G和Ig M，可使粘液穿透的聚乙二醇化纳米粒被广泛捕获，可移动颗粒的比例从95%以上分别减少到仅有34%和7%。令人惊讶的是，我们没有观察到任何一种抗体引起的显著凝集，这表明颗粒固定是由粘蛋白纤维与结合到单个纳米颗粒上的免疫球蛋白或免疫球蛋白M之间的粘性交联引起的。重要的是，添加相应的对照抗体并没有减缓聚乙二醇化纳米颗粒的速度，证实了抗聚乙二醇化纳米颗粒特异性地结合并捕获了聚乙二醇化纳米颗粒。最后，我们发现，捕获的聚乙二醇化纳米颗粒大部分保留在小鼠阴道的管腔粘液层中，即使在低渗配方中也是如此，这种低渗配方会导致未捕获的颗粒被流经粘液的水(平流)一路吸引到上皮表面。这些结果强调了对于应用于粘膜表面的聚乙二醇化治疗药物和生物材料，阐明粘膜抗聚乙二醇化免疫反应的潜在重要性。
Antibodies that specifically bind polyethylene glycol (PEG) can lead to rapid elimination of PEGylated therapeutics from the systemic circulation. We have recently shown that virus-binding IgG can immobilize viruses in mucus via multiple low-affinity crosslinks between IgG and mucins. However, it remains unclear whether anti-PEG antibodies in mucus may also alter the penetration and consequently biodistribution of PEGylated nanoparticles delivered to mucosal surfaces. We found that both anti-PEG IgG and IgM can readily bind nanoparticles that were densely coated with PEG polymer to minimize adhesive interactions with mucus constituents. Addition of anti-PEG IgG and IgM into mouse cervicovaginal mucus resulted in extensive trapping of mucus-penetrating PEGylated nanoparticles, with the fraction of mobile particles reduced from over 95% to only 34% and 7% with anti-PEG IgG and IgM, respectively. Surprisingly, we did not observe significant agglutination induced by either antibody, suggesting that particle immobilization is caused by adhesive crosslinks between mucin fibers and IgG or IgM bound to individual nanoparticles. Importantly, addition of corresponding control antibodies did not slow the PEGylated nanoparticles, confirming anti-PEG antibodies specifically bound to and trapped the PEGylated nanoparticles. Finally, we showed that trapped PEGylated nanoparticles remained largely in the luminal mucus layer of the mouse vagina even when delivered in hypotonic formulations that caused untrapped particles to be drawn by the flow of water (advection) through mucus all the way to the epithelial surface. These results underscore the potential importance of elucidating mucosal anti-PEG immune responses for PEGylated therapeutics and biomaterials applied to mucosal surfaces.
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影响因子：
16.1
作者：
Lai, Samuel K.;Wang, Ying-Ying;Hanes, Justin
通讯作者：
Hanes, Justin
影响因子：
2
作者：
Hashimoto, Yosuke;Shimizu, Taro;Kiwada, Hiroshi
通讯作者：
Kiwada, Hiroshi
影响因子：
2.7
作者：
Ehrlich, George K.;Michel, Hanspeter;Malick, A. Waseem
通讯作者：
Malick, A. Waseem
影响因子：
10.8
作者：
Ishida, T;Ichihara, M;Kiwada, H
通讯作者：
Kiwada, H
DOI：
10.1016/0005-2736(91)90246-5
发表时间：
1991-07-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
ALLEN, TM;HANSEN, C;YAUYOUNG, A
通讯作者：
YAUYOUNG, A