Department of Pathobiological Sciences, University of Wisconsin-Madison, Wisconsin-Madison, Wisconsin, 53706.
Pfizer, St. Louis, Missouri, 63198.
J Biomed Mater Res A. 2017 Oct;105(10):2762-2771. doi: 10.1002/jbm.a.36128. Epub 2017 Jul 6.
Rational design of adjuvants and delivery systems will promote development of next-generation vaccines to control emerging and re-emerging diseases. To accomplish this, understanding the immune-enhancing properties of new adjuvants relative to those induced by natural infections can help with the development of pathogen-mimicking materials that will effectively initiate innate immune signaling cascades. In this work, the surfaces of polyanhydride nanoparticles composed of sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy) hexane were decorated with an ethylene diamine spacer partially modified with either a glycolic acid linker or an α-1,2-linked di-mannopyranoside (di-mannose) to confer "pathogen-like" properties and enhance adjuvanticity. Co-incubation of linker-modified nanoparticles with dendritic cells (DCs) elicited significant increases in surface expression of MHC I, MHC II, CD86, and CD40, and enhanced secretion of IL-6, IL-12p40, and TNF-α. An 800% increase in uptake of ethylene-diamine-spaced, linker and di-mannose functionalized polyanhydride nanoparticles was also observed. Together, our data showed that linker-functionalized polyanhydride nanoparticles demonstrate similar patterns of uptake, intracellular trafficking, particle persistence, and innate activation as did DCs exposed to Yersinia pestis or Escherichia coli. These results set the stage for rational selection of adjuvant chemistries to induce pathogen-mimicking immune responses. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2762-2771, 2017.
佐剂和递送系统的合理设计将促进新一代疫苗的开发，以控制新发和再现传染病。为了实现这一目标，了解新佐剂相对于自然感染诱导的免疫增强特性，可以帮助开发模拟病原体的材料，从而有效引发先天免疫信号级联反应。在这项工作中，由癸二酸（SA）和 1,6-双（对羧基苯氧基）己烷组成的聚酸酐纳米粒子的表面用乙二胺间隔物修饰，该间隔物部分用乙交酯连接剂或α-1,2-连接的二甘露吡喃糖苷（二甘露糖）修饰，以赋予“病原体样”性质并增强佐剂活性。连接剂修饰的纳米粒子与树突状细胞（DC）共孵育可显著增加 MHC I、MHC II、CD86 和 CD40 的表面表达，并增强 IL-6、IL-12p40 和 TNF-α 的分泌。还观察到乙二胺间隔、连接剂和二甘露糖功能化聚酸酐纳米粒子的摄取增加了 800%。我们的数据表明，连接基功能化聚酸酐纳米粒子与暴露于鼠疫耶尔森菌或大肠杆菌的 DC 一样，表现出相似的摄取、细胞内转运、颗粒持久性和先天激活模式。这些结果为合理选择佐剂化学物质以诱导模拟病原体的免疫反应奠定了基础。©2017 年 Wiley 期刊出版公司生物医学材料研究杂志 A 部分：105A：2762-2771，2017 年。
