Dey Raja, Xia Yan, Nieh Mu-Ping, Burkhard Peter
Institute of Materials Science, University of Connecticut, Storrs, Connecticut 06269-3136, United States.
Department of Chemical & Biomolecular Engineering, University of Connecticut, Storrs, Connecticut 06269-3222, United States.
ACS Biomater Sci Eng. 2017 May 8;3(5):724-732. doi: 10.1021/acsbiomaterials.6b00243. Epub 2016 Aug 10.
Nanoparticles are getting a great deal of attention in the rapidly developing field of nanomedicine. For example they can be used as drug delivery systems, for imaging applications, or as carriers for synthetic vaccines. Protein-based nanoparticles offer the advantage of biocompatibility and biodegradability thus avoiding some of the major toxicity concerns with nanoparticle associated approaches. Our group has developed self-assembling peptide/protein nanopartices (SAPNs) that are built up from two coiled-coil oligomerization domains joined by a linker region and used them to design subunit vaccines. For drug delivery approaches the SAPNs need to be as small as possible to avoid strong immune responses that could possibly even lead to anaphylaxis. Here we used a computational and biophysical approach to minimize the size of the SAPNs for their use as drug delivery system. We tested different charge distributions on the pentameric and trimeric coiled-coils in silico with molecular dynamics simulations to down-select an optimal design. This design was then investigated in vitro by biophysical methods and we were able to engineer a minimal SAPN of only 11 nm in diameter. Such minimal-sized SAPNs offer new avenues for a safer development as drug delivery systems or other biomedical applications.
在快速发展的纳米医学领域，纳米颗粒正受到广泛关注。例如，它们可用作药物递送系统、用于成像应用或作为合成疫苗的载体。基于蛋白质的纳米颗粒具有生物相容性和生物可降解性的优势，从而避免了与纳米颗粒相关方法的一些主要毒性问题。我们的团队开发了自组装肽/蛋白质纳米颗粒（SAPNs），它由两个通过连接区连接的卷曲螺旋寡聚化结构域组成，并将其用于设计亚单位疫苗。对于药物递送方法，SAPNs需要尽可能小，以避免可能甚至导致过敏反应的强烈免疫反应。在这里，我们使用了一种计算和生物物理方法来最小化用作药物递送系统的SAPNs的尺寸。我们通过分子动力学模拟在计算机上测试了五聚体和三聚体卷曲螺旋上不同的电荷分布，以筛选出最佳设计。然后通过生物物理方法在体外对该设计进行研究，我们成功构建了直径仅为11nm的最小SAPN。这种最小尺寸的SAPNs为作为药物递送系统或其他生物医学应用的更安全开发提供了新途径。
