Divisions of Rheumatology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Biol Chem. 2011 Jan 7;286(1):123-30. doi: 10.1074/jbc.M110.180760. Epub 2010 Nov 3.
A wide variety of nanomaterials are currently being developed for use in the detection and treatment of human diseases. However, there is no systematic way to measure and predict the action of such materials in biological contexts. Lipid-encapsulated nanoparticles (NPs) are a class of nanomaterials that includes the liposomes, the most widely used and clinically proven type of NPs. Liposomes can, however, activate the complement system, an important branch of innate immunity, resulting in undesirable consequences. Here, we describe the complement response to lipid-encapsulated NPs that are functionalized on the surface with various lipid-anchored gadolinium chelates. We developed a quantitative approach to examine the interaction of NPs with the complement system using in vitro assays and correlating these results with those obtained in an in vivo mouse model. Our results indicate that surface functionalization of NPs with certain chemical structures elicits swift complement activation that is initiated by a natural IgM antibody and propagated via the classical pathway. The intensity of the response is dependent on the chemical structures of the lipid-anchored chelates and not zeta potential effects alone. Moreover, the extent of complement activation may be tempered by complement inhibiting regulatory proteins that bind to the surface of NPs. These findings represent a step forward in the understanding of the interactions between nanomaterials and the host innate immune response and provide the basis for a systematic structure-activity relationship study to establish guidelines that are critical to the future development of biocompatible nanotherapeutics.
目前正在开发各种纳米材料用于人类疾病的检测和治疗。然而，目前还没有系统的方法来测量和预测这些材料在生物环境中的作用。脂质体包被的纳米颗粒（NPs）是一类纳米材料，包括脂质体，这是最广泛使用和临床验证的 NPs 类型。然而，脂质体可以激活补体系统，这是先天免疫的一个重要分支，从而导致不良后果。在这里，我们描述了脂质体包被的 NPs 与补体系统的相互作用，这些 NPs 的表面用各种脂质锚定的钆螯合物进行了功能化。我们开发了一种定量方法来使用体外测定来检查 NPs 与补体系统的相互作用，并将这些结果与在体内小鼠模型中获得的结果相关联。我们的结果表明，NPs 表面的某些化学结构的功能化会引发迅速的补体激活，这种激活是由天然 IgM 抗体引发的，并通过经典途径传播。反应的强度取决于脂质锚定螯合物的化学结构，而不仅仅是 zeta 电位效应。此外，补体激活的程度可能会受到与 NPs 表面结合的补体抑制调节蛋白的调节。这些发现代表了在理解纳米材料与宿主先天免疫反应之间相互作用方面的一个进步，并为建立对未来生物相容性纳米治疗学的发展至关重要的系统结构-活性关系研究提供了基础。
