Variable Antibody-dependent Activation of Complement by Functionalized Phospholipid Nanoparticle Surfaces
Variable Antibody-dependent Activation of Complement by Functionalized Phospholipid Nanoparticle Surfaces
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DOI：
10.1074/jbc.m110.180760
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发表时间：
2011-01-07
影响因子：
4.8
通讯作者：
Hourcade, Dennis E.
中科院分区：
文献类型：
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作者：
Pham, Christine T. N.;Mitchell, Lynne M.;Hourcade, Dennis E.
目前正在开发各种各样的纳米材料，用于检测和治疗人类疾病。然而，没有系统的方法来测量和预测这些材料在生物学背景下的作用。脂质包封纳米颗粒（NP）是一类纳米材料，包括脂质体，最广泛使用和临床证明的NP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，导致不希望的后果。在这里，我们描述了补体对脂质包封的NP的反应，所述脂质包封的NP在表面上用各种脂质锚定的钆螯合物官能化。我们开发了一种定量的方法来检查使用在体外测定的纳米粒子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。我们的研究结果表明，具有某些化学结构的纳米颗粒的表面功能化可以迅速激活补体，这种激活是由天然IgM抗体引发的，并通过经典途径传播。响应的强度取决于脂质锚定螯合物的化学结构，而不是单独的zeta电位效应。此外，补体激活的程度可以通过结合到NP表面的补体抑制调节蛋白来缓和。这些发现代表了理解纳米材料与宿主先天免疫反应之间相互作用的一个进步，并为系统的结构-活性关系研究提供了基础，以建立对生物相容性纳米治疗药物未来发展至关重要的指导方针。
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.