Benasutti Halli, Wang Guankui, Vu Vivian P, Scheinman Robert, Groman Ernest, Saba Laura, Simberg Dmitri
Translational Bio-Nanosciences Laboratory, ‡Colorado Center for Nanomedicine and Nanosafety, §The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, ∥Systems Genetics and Bioinformatics Laboratory, and ⊥Center for Translational Pharmacokinetics and Pharmacogenomics, University of Colorado Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, Colorado 80045, United States.
Bioconjug Chem. 2017 Nov 15;28(11):2747-2755. doi: 10.1021/acs.bioconjchem.7b00496. Epub 2017 Nov 1.
Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15-30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical difference between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual's response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.
纳米颗粒被补体C3成分调理（包被）是触发免疫清除以及下游过敏和促炎反应的重要机制。普通人群中补体C3与纳米颗粒结合的变异性尚未得到研究。我们检测了健康人血清中补体C3与葡聚糖超顺磁性氧化铁纳米颗粒（超顺磁性氧化铁纳米蠕虫，SPIO NWs，58和110 nm）以及临床批准的纳米颗粒（羧甲基葡聚糖氧化铁非格司亭（Feraheme，28 nm）、高度聚乙二醇化脂质体阿霉素（LipoDox，88 nm）和最低限度聚乙二醇化脂质体伊立替康（Onivyde，120 nm））的结合情况。SPIO NWs在受试者之间的C3结合变异性最高（n = 47），C3水平范围为15至30倍。LipoDox（n = 12）和Feraheme（n = 18）在受试者之间的变异性最低（约1.5倍范围），而Onivyde（n = 18）在受试者之间的变异性处于中等水平（2倍范围）。男性和女性之间没有统计学差异，且与年龄无关。结构和化学性质相似的小尺寸和大尺寸SPIO NWs之间的补体反应存在显著相关性，但SPIO NWs与其他类型纳米颗粒之间以及LipoDox和Onivyde之间的相关性不显著。计算得出的每个纳米颗粒结合的C3分子平均数与流体动力学直径相关，但在LipoDox中有所降低，这可能是由于聚乙二醇包被。本研究的结论是：（1）所有纳米颗粒在普通人群中均表现出C3调理作用的变异性；（2）不能基于另一种纳米颗粒可靠地预测个体对一种纳米颗粒的反应；（3）每个纳米颗粒的C3分子平均数取决于尺寸和表面包被。这些结果为提高纳米医学安全性提供了新策略。
