Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States.
Nanovaccine Institute, Iowa State University, Ames, Iowa 50011-1098, United States.
ACS Biomater Sci Eng. 2020 Jan 13;6(1):265-276. doi: 10.1021/acsbiomaterials.9b01427. Epub 2020 Jan 3.
There is a currently a need to develop adjuvants that are best suited to simultaneously enhance immune responses, induce immunologic memory, improve patient compliance (i.e., reduce doses and inflammation), and provide vaccine shelf stability for stockpiling and global deployment to challenging environments. Biodegradable polyanhydrides have been investigated extensively to overcome such challenges. It has been shown that controlling copolymer composition can result in chemistry-dependent immunomodulatory capabilities. These studies have revealed that copolymers rich in sebacic acid (SA) are highly internalized by antigen presenting cells and confer improved shelf stability of encapsulated proteins, while copolymers rich in 1,8-bis(-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) also exhibit enhanced internalization by and activation of antigen presenting cells (APCs), in addition to providing superior retention of protein stability following encapsulation and release. However, to date, CPTEG:SA copolymers have not been synthesized and described. In this work, we hypothesized that new copolymers composed of CPTEG and SA would combine the advantages of both monomers in terms of enhanced thermal properties, maintaining antigenicity of encapsulated proteins following nanoparticle synthesis, and superior cellular internalization and activation by APCs, demonstrated by the upregulation of costimulatory markers CD80, CD86, and CD40, as well as the secretion of proinflammatory cytokines IL-6, IL-1β, and TNF-α. Herein, we describe the synthesis and design of novel CPTEG:SA nanoparticles with improved thermal properties, payload stability, and internalization by antigen presenting cells for applications in vaccine delivery. The performance of these new CPTEG:SA formulations was compared to that of traditional polyanhydride copolymers.
目前需要开发一种佐剂，这种佐剂最好能够同时增强免疫反应、诱导免疫记忆、提高患者顺应性（即减少剂量和炎症），并为储备和在具有挑战性的环境中全球部署提供疫苗货架稳定性。可生物降解的聚酐已被广泛研究以克服这些挑战。已经表明，控制共聚物组成可以导致依赖于化学的免疫调节能力。这些研究表明，富含癸二酸（SA）的共聚物被抗原呈递细胞高度内化，并赋予包封蛋白更高的货架稳定性，而富含 1,8-双（-羧基苯氧基）-3,6-二氧杂辛烷（CPTEG）的共聚物也通过和抗原呈递细胞（APCs）的激活，除了在封装和释放后提供更好的蛋白质稳定性保留。然而，迄今为止，尚未合成和描述 CPTEG:SA 共聚物。在这项工作中，我们假设由 CPTEG 和 SA 组成的新共聚物将在增强热性能、保持纳米颗粒合成后包封蛋白的抗原性以及通过 APC 增强细胞内化和激活方面结合两种单体的优势，通过上调共刺激标志物 CD80、CD86 和 CD40 以及促炎细胞因子 IL-6、IL-1β 和 TNF-α 的分泌来证明这一点。在此，我们描述了具有改进的热性能、有效负载稳定性和抗原呈递细胞内化能力的新型 CPTEG:SA 纳米粒子的合成和设计，可应用于疫苗传递。这些新型 CPTEG:SA 制剂的性能与传统聚酐共聚物进行了比较。
