Acta Biomaterialia ( IF 9.4 ) Pub Date : 2018-09-06 , DOI: 10.1016/j.actbio.2018.09.001 William J Kelley 1 , Catherine A Fromen 1 , Genesis Lopez-Cazares 1 , Omolola Eniola-Adefeso 1
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Targeted drug carriers are attractive for the delivery of therapeutics directly to the site of a disease, reducing systemic side effects and enhancing the efficacy of therapeutic molecules. However, the use of particulate carriers for drug delivery comes with its own set of challenges and barriers. Among these, a great deal of research effort has focused on protecting carriers from clearance by phagocytes via altering carrier surface chemistry, mostly with the use of polyethylene glycol (PEG) chain coatings. However, few papers have explored the effects of PEGylation on uptake by freshly obtained primary human phagocytes in physiological conditions. In this work, we investigate the effect of PEGylation on particle uptake by primary human neutrophils in vitro and compare these effects to several cell lines and other model phagocytic cells systems. We find that human neutrophils in whole blood preferentially phagocytose PEGylated particles (e.g., ∼40% particle positive neutrophils for PEGylated versus ∼20% for carboxylated polystyrene microspheres) and that this effect is linked to factors present in human plasma. Model phagocytes internalized PEGylated particles less efficiently or equivalently to carboxylated particles in culture medium but preferentially phagocytosed PEGylated particles in the human plasma (e.g., ∼86% versus ∼63% PEGylated versus carboxylated particle positive cells, respectively). These findings have significant implications for the efficacy of PEGylation in designing long-circulating drug carriers, as well as the need for thorough characterization of drug carrier platforms in a wide array of in vitro and in vivo assays.
Statement of Significance
The work in this manuscript is highly significant to the field of drug delivery, as it explores in-depth the effects of polyethylene glycol (PEG) coatings, which are frequently used to prevent phagocytic clearance of particulate drug carriers, on the phagocytosis of such carriers by neutrophils, the most abundant leukocyte in blood circulation. Surprisingly, we find that PEGylation enhances uptake by primary human neutrophils, specifically in the presence of human plasma. This result suggests that PEGylation may not confer the benefits in humans once thought, and may help to explain why PEG has not become the “magic bullet” it was once thought to be in the field of particulate drug delivery.
中文翻译：
模型药物载体的聚乙二醇化增强原代人中性粒细胞的吞噬作用
靶向药物载体对于将治疗药物直接递送至疾病部位、减少全身副作用并增强治疗分子的功效具有吸引力。然而，使用颗粒载体进行药物输送也有其自身的一系列挑战和障碍。其中，大量的研究工作集中在通过改变载体表面化学性质（主要是使用聚乙二醇（PEG）链涂层）来保护载体免受吞噬细胞的清除。然而，很少有论文探讨聚乙二醇化对生理条件下新鲜获得的原代人类吞噬细胞摄取的影响。在这项工作中，我们研究了聚乙二醇化对体外原代人类中性粒细胞摄取颗粒的影响，并将这些影响与几种细胞系和其他模型吞噬细胞系统进行了比较。我们发现全血中的人类中性粒细胞优先吞噬聚乙二醇化颗粒（例如，聚乙二醇化颗粒阳性中性粒细胞为~40%，而羧化聚苯乙烯微球为~20%），并且这种效应与人血浆中存在的因素有关。模型吞噬细胞内化聚乙二醇化颗粒的效率低于或相当于培养基中的羧化颗粒，但优先吞噬人血浆中的聚乙二醇化颗粒（例如，聚乙二醇化颗粒阳性细胞与羧化颗粒阳性细胞分别为~86%和~63%）。这些发现对于聚乙二醇化在设计长循环药物载体中的功效以及在各种体外和体内测定中对药物载体平台进行彻底表征的需要具有重要意义。
重要性声明
该手稿中的工作对于药物输送领域具有非常重要的意义，因为它深入探讨了经常用于防止颗粒药物载体的吞噬清除的聚乙二醇（PEG）涂层对此类载体的吞噬作用的影响由嗜中性粒细胞（血液循环中最丰富的白细胞）产生。令人惊讶的是，我们发现聚乙二醇化增强了原代人中性粒细胞的摄取，特别是在人血浆存在的情况下。这一结果表明，聚乙二醇化可能不会给人类带来曾经认为的好处，并且可能有助于解释为什么聚乙二醇没有成为曾经被认为是颗粒药物输送领域的“灵丹妙药”。
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