Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Translational Bio-Nanosciences Laboratory, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J Control Release. 2021 Oct 10;338:548-556. doi: 10.1016/j.jconrel.2021.08.048. Epub 2021 Sep 2.
The complement system plays a key role in opsonization and immune clearance of engineered nanoparticles. Understanding the efficiency, inter-subject, and inter-strain differences of complement opsonization in preclinical species can help with translational nanomedicine development and improve our ability to model complement response in humans. Dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles and a wide range of non-magnetic iron oxide nanoparticle formulations are widely used in magnetic resonance imaging and as clinically approved iron supplements. Previously we found that opsonization of SPIO nanoworms (NW) with the third complement protein (C3) proceeds mostly via the alternative pathway in humans, and via the lectin pathway in mice. Here, we studied the pathway and efficiency of opsonization of 106 nm SPIO NW with C3 in different preclinical species and commonly used laboratory strains. In sera of healthy human donors (n = 6), C3 opsonization proceeded exclusively through the alternative pathway. On the other hand, the C3 opsonization in dogs (6 breeds), rats (4 strains) and mice (5 strains) sera was either partially or completely dependent on the complement Ca-sensitive pathways (lectin and/or classical). Specifically, C3 opsonization in sera of Long Evans rat strain, and mouse strains widely used in nanomedicine research (BALB/c, C57BL/6 J, and A/J) was only through the Ca-dependent pathways. Dogs and humans had the highest between-subject variability in C3 opsonization levels, while rat and mouse sera showed the lowest between-strain variability. Furthermore, using a panel of SPIO nanoparticles of different sizes and dextran coatings, we found that the level of C3 opsonization (C3 molecules per milligram Fe) in human sera was lower than in animal sera. At the same time, there was a strong predictive value of complement opsonization in dog and rat sera; nanoparticles with higher C3 deposition in animals showed higher deposition in humans, and vice versa. Notably, the opsonization decreased with decreasing size in all sera. The studies highlight the importance of the consideration of species and strains for predicting human complement responses (opsonization) towards nanomedicines.
补体系统在工程纳米粒子的调理和免疫清除中起着关键作用。了解补体调理在临床前物种中的效率、个体间和种间差异，有助于转化纳米医学的发展，并提高我们在人类中模拟补体反应的能力。葡聚糖涂层超顺磁性氧化铁（SPIO）纳米粒子和广泛的非磁性氧化铁纳米粒子制剂广泛用于磁共振成像和临床批准的铁补充剂。此前，我们发现 SPIO 纳米线（NW）与补体蛋白（C3）的调理主要通过人类的替代途径进行，而通过小鼠的凝集素途径进行。在这里，我们研究了 C3 在不同临床前物种和常用实验室品系中对 106nm SPIO NW 的调理途径和效率。在健康人类供体血清（n=6）中，C3 调理仅通过替代途径进行。另一方面，狗（6 个品种）、大鼠（4 个品系）和小鼠（5 个品系）血清中的 C3 调理要么部分依赖于补体 Ca 敏感途径（凝集素和/或经典途径），要么完全依赖于补体 Ca 敏感途径。具体来说，Long Evans 大鼠品系和广泛用于纳米医学研究的小鼠品系（BALB/c、C57BL/6J 和 A/J）的 C3 调理仅通过 Ca 依赖性途径进行。狗和人类在 C3 调理水平上的个体间变异性最高，而大鼠和小鼠血清的种间变异性最低。此外，使用不同大小和葡聚糖涂层的 SPIO 纳米粒子的面板，我们发现人血清中的 C3 调理水平（每毫克铁的 C3 分子数）低于动物血清。同时，狗和大鼠血清中的补体调理具有很强的预测价值；在动物中具有更高 C3 沉积的纳米粒子在人中显示出更高的沉积，反之亦然。值得注意的是，所有血清中的调理作用均随粒径的减小而降低。这些研究强调了考虑物种和品系对于预测纳米药物对人类补体反应（调理）的重要性。
