Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake.
Modulatory Role of Surface Coating of Superparamagnetic Iron Oxide Nanoworms in Complement Opsonization and Leukocyte Uptake.
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DOI：
10.1021/acsnano.5b05061
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发表时间：
2015-11-24
期刊：
影响因子：
17.1
通讯作者：
Simberg D
中科院分区：
文献类型：
--
作者：
Inturi S;Wang G;Chen F;Banda NK;Holers VM;Wu L;Moghimi SM;Simberg D
尽管纳米技术在诊断成像和药物递送方面取得了快速进展，但工程纳米载体仍然表现出严重缺乏血液相容性。因此，当全身注射时，纳米颗粒被血液白细胞和血小板热切地识别，但免疫识别的机制尚不清楚，减轻这些现象的策略仍未得到充分探索。利用超顺磁性右旋糖酐氧化铁（SPIO）纳米蠕虫（NWs），我们在体外证明了正常小鼠和肿瘤小鼠的淋巴细胞、中性粒细胞和单核细胞的高效和主要补体依赖性摄取。在野生型小鼠静脉注射后，血液白细胞和血小板被磁性标记，而补体c3缺陷小鼠的标记率降低了95%。使用健康和癌症患者供体的血细胞，我们证明中性粒细胞、单核细胞、淋巴细胞和嗜酸性粒细胞摄取SPIO NWs，并且被EDTA（一种通用的补体抑制剂）和antiproperdin抗体（补体系统替代途径的抑制剂）阻止摄取。环氧氯丙烷对SPIO NWs表面的交联和水凝胶作用降低了小鼠血清中C3的活化，从而使小鼠白细胞对其的摄取减少了70%以上。值得注意的是，交联颗粒在人血清中没有显示出C3的活化减少，但在人白细胞中显示出明显减少（超过60%）的摄取。交联纳米颗粒的残留吸收被EDTA完全阻断。这些发现证明了补体介导的纳米颗粒被白细胞识别和摄取的物种差异，并进一步表明补体替代途径的抑制剂和纳米颗粒表面涂层可以改善人类血液相容性。这些结果为纳米药物的血液相容性机制提供了重要的见解。
Notwithstanding rapid advances of nanotechnology in diagnostic imaging and drug delivery, the engineered nanocarriers still exhibit substantial lack of hemocompatibility. Thus, when injected systemically, nanoparticles are avidly recognized by blood leukocytes and platelets, but the mechanisms of immune recognition are not well understood and strategies to mitigate these phenomena remain underexplored. Using superparamagnetic dextran iron oxide (SPIO) nanoworms (NWs) we demonstrate an efficient and predominantly complement-dependent uptake by mouse lymphocytes, neutrophils and monocytes from normal and tumor bearing mice in vitro. Following intravenous injection into wild type mice, blood leukocytes as well as platelets became magnetically labeled, while the labeling was decreased by 95% in complement C3-deficient mice. Using blood cells from healthy and cancer patient donors, we demonstrated that neutrophils, monocytes, lymphocytes and eosinophils took up SPIO NWs, and the uptake was prevented by EDTA (a general complement inhibitor) and by antiproperdin antibody (an inhibitor of the alternative pathway of the complement system). Cross-linking and hydrogelation of SPIO NWs surface by epichlorohydrin decreased C3 opsonization in mouse serum, and consequently reduced the uptake by mouse leukocytes by more than 70% in vivo. Remarkably, the cross-linked particles did not show a decrease in C3 opsonization in human serum, but showed a significant decrease (over 60%) of the uptake by human leukocytes. The residual uptake of cross-linked nanoparticles was completely blocked by EDTA. These findings demonstrate species differences in complement-mediated nanoparticle recognition and uptake by leukocytes, and further show that human hemocompatibility could be improved by inhibitors of complement alternative pathway and by nanoparticle surface coating. These results provide important insights into the mechanisms of hemocompatibility of nanomedicines.