Department of Chemical and Biological Engineering, Iowa State University, Ames, Iowa, 50011.
Department of Veterinary Microbiology and Preventive Medicine, Iowa State University, Ames, Iowa, 50011.
J Biomed Mater Res A. 2019 Aug;107(8):1754-1762. doi: 10.1002/jbm.a.36691. Epub 2019 Apr 29.
Injectable thermogelling polymers have been recently investigated as novel adjuvants and delivery systems for next generation vaccines. As research into natural and synthetic biocompatible polymers progresses, the safety and biocompatibility of these compounds is of paramount importance. We have developed cationic pentablock copolymer (PBC) vaccine adjuvants based on Pluronic F127, a thermogelling triblock copolymer that has been approved by the FDA for multiple applications, and methacrylated poly(diethyl amino)ethyl methacrylate outer blocks. These novel materials have been demonstrated to effectively create an antigen depot, minimally impact antigen stability, and enhance the immune response to antigens (i.e., adjuvanticity) in mice. In this work, we investigated the safety and biocompatibility of the parent triblock Pluronic gels and the cationic PBC gels in mice. Histological analysis showed no injection site reactions and no damage to the liver or kidneys was observed upon administering the block copolymer formulations. However, the subcutaneous injection of a thermogelling Pluronic solution induced increased levels of lipids in the blood, with no further deleterious effects observed from the addition of the cationic outer blocks. This hyperlipidemia resolved within 30 days after the administration of the Pluronic formulation. To mitigate this adverse effect, the vaccine adjuvant formulations were modified by adding poly(vinyl alcohol), which allowed gelation, while reducing the amount of Pluronic in the formulation. This modified formulation abrogated the observed hyperlipidemia and no adverse effects were observed in the serum through biomarker analysis or at the injection site (i.e., inflammation) in comparison to the responses induced by administration of saline or incomplete Freund's adjuvant. These studies provide a foundation to developing these gels as adjuvants for next generation vaccines. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1754-1762, 2019.
最近，人们研究了可注射的温敏聚合物作为新型佐剂和下一代疫苗的递药系统。随着对天然和合成生物相容性聚合物的研究进展，这些化合物的安全性和生物相容性至关重要。我们已经开发了基于 Pluronic F127 的阳离子五嵌段共聚物（PBC）疫苗佐剂，Pluronic F127 是一种已被 FDA 批准用于多种应用的温敏两亲性嵌段共聚物，以及甲基丙烯酰化聚（二乙氨基）乙基甲基丙烯酸酯的外嵌段。这些新型材料已被证明能有效地形成抗原库，最小化地影响抗原稳定性，并增强小鼠对抗原的免疫应答（即佐剂活性）。在这项工作中，我们研究了母体两亲性 Pluronic 凝胶和阳离子 PBC 凝胶在小鼠中的安全性和生物相容性。组织学分析显示，注射部位无反应，给予嵌段共聚物制剂后未观察到肝或肾损伤。然而，温敏性 Pluronic 溶液的皮下注射会导致血液中脂质水平升高，但在外嵌段加入阳离子后没有观察到进一步的有害影响。这种高脂血症在 Pluronic 制剂给药后 30 天内得到解决。为了减轻这种不良反应，通过添加聚乙烯醇（PVA）对疫苗佐剂制剂进行了修饰，使其凝胶化，同时减少制剂中的 Pluronic 含量。与生理盐水或不完全弗氏佐剂给药引起的反应相比，这种修饰后的制剂消除了观察到的高脂血症，并且在血清生物标志物分析或注射部位（即炎症）均未观察到不良反应。这些研究为将这些凝胶开发为下一代疫苗佐剂奠定了基础。© 2019 威利父子公司
