Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels
Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels
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DOI：
10.1002/jbm.a.36691
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Mallapragada, Surya K.
中科院分区：
文献类型：
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作者：
Adams, Justin R.;Senapati, Sujata;Mallapragada, Surya K.
可注射的热胶凝聚合物最近被研究作为新一代疫苗的新型佐剂和递送系统。随着对天然和合成生物相容性聚合物的研究的进展，这些化合物的安全性和生物相容性至关重要。我们开发了基于Pluronic F127（一种已获得FDA批准用于多种应用的热凝胶三嵌段共聚物）和甲基丙烯酸酯化聚（二乙氨基）甲基丙烯酸乙酯外嵌段的阳离子五嵌段共聚物（PBC）疫苗佐剂。这些新材料已被证明有效地产生抗原贮库，最小限度地影响抗原稳定性，并增强对抗原的免疫应答（即，佐剂性）。在这项工作中，我们研究了母体三嵌段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，在给予嵌段共聚物制剂后，未观察到注射部位反应和肝或肾损伤。然而，皮下注射热凝胶化Pluronic溶液诱导血液中脂质水平升高，添加阳离子外嵌段未观察到进一步的有害作用。该高脂血症在Pluronic制剂给药后30天内消退。为了减轻这种不利影响，通过添加聚（乙烯醇）来修改疫苗佐剂制剂，这允许凝胶化，同时减少制剂中Pluronic的量。该改良制剂消除了观察到的高脂血症，并且通过生物标志物分析在血清中或在注射部位（即，与通过施用盐水或不完全弗氏佐剂诱导的应答相比，这些研究为开发这些凝胶作为下一代疫苗的佐剂提供了基础。(c)2019 Wiley Periodicals，Inc. J Biomed Mater Res Part A：107A：1754-1762，2019.
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. (c) 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1754-1762, 2019.