Nanomedicine Laboratory, Centre for Pharmaceutical Nanotechnology and Nanotoxicology, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark.
Department of Chemical Engineering and Center for Bioengineering, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
Nat Nanotechnol. 2017 Jul;12(6):589-594. doi: 10.1038/nnano.2017.47. Epub 2017 Apr 10.
Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration.
静脉注射的纳米药物，包括聚乙二醇化纳米颗粒，会在敏感的人体受试者中引起不良心肺反应，而这些反应在猪身上具有高度可重复性。尽管其潜在机制尚不清楚，但补体系统和反应性巨噬细胞都可能起作用。在这里，我们展示了在介导猪的不良心肺窘迫中，强大的肺血管内巨噬细胞清除纳米颗粒的主导作用和重要性，而与补体激活无关。具体来说，我们通过两种独立的方法表明，延迟注射后最初几分钟内巨噬细胞对颗粒的识别可以克服猪的不良反应。首先，我们将颗粒的形状从球形（触发心肺窘迫）改变为棒状或盘状形态。其次，我们将球体物理附着在红细胞表面。这些策略与常用的隐身工程方法（如用聚乙二醇和/或免疫调节剂对纳米颗粒表面进行功能化）不同，可防止强大的巨噬细胞识别，从而减少或缓解与纳米药物给药相关的不良心肺窘迫。
