A macromolecular delivery vehicle for protein-based vaccines:: Acid-degradable protein-loaded microgels
A macromolecular delivery vehicle for protein-based vaccines:: Acid-degradable protein-loaded microgels
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DOI：
10.1073/pnas.0930644100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Fréchet, JMJ
中科院分区：
文献类型：
--
作者：
Murthy, N;Xu, MC;Fréchet, JMJ
基于蛋白质的疫苗的开发仍然是免疫学和药物递送领域的主要挑战。尽管已经鉴定了许多蛋白质抗原可以产生对感染性病原体的免疫力，但是由于递送问题，基于蛋白质抗原的疫苗的开发成功有限。本文合成了一种酸敏感的微凝胶材料，用于蛋白质疫苗的开发。这些微凝胶的化学设计使得它们在抗原呈递细胞（APC）的吞噬体中发现的温和酸性条件下降解。微凝胶的快速切割通过胶体渗透机制导致吞噬体破坏，将蛋白质抗原释放到APC细胞质中用于I类抗原呈递。采用反相乳液聚合法，将卵清蛋白包裹在粒径为200-500 nm的微凝胶中，并合成了一种酸降解交联剂。卵清蛋白以pH依赖性方式从酸可降解微凝胶中释放;例如，含有卵清蛋白的微凝胶在pH 5.0下5小时后释放80%的其包封的蛋白质，但在pH 7.4下仅释放10%。吞噬含有卵清蛋白的酸可降解微凝胶的APC能够激活卵清蛋白特异性细胞毒性T淋巴细胞。因此，本文中开发的酸可降解的微凝胶应该作为针对病毒和肿瘤的疫苗的递送载体找到应用，其中细胞毒性T淋巴细胞的活化是免疫力发展所必需的。
The development of protein-based vaccines remains a major challenge in the fields of immunology and drug delivery. Although numerous protein antigens have been identified that can generate immunity to infectious pathogens, the development of vaccines based on protein antigens has had limited success because of delivery issues. In this article, an acid-sensitive microgel material is synthesized for the development of protein-based vaccines. The chemical design of these microgels is such that they degrade under the mildly acidic conditions found in the phagosomes of antigen-presenting cells (APCs). The rapid cleavage of the microgels leads to phagosomal disruption through a colloid osmotic mechanism, releasing protein antigens into the APC cytoplasm for class I antigen presentation. Ovalbumin was encapsulated in microgel particles, 200-500 nm in diameter, prepared by inverse emulsion polymerization with a synthesized acid-degradable crosslinker. Ovalbumin is released from the acid-degradable microgels in a pH-dependent manner; for example, microgels containing ovalbumin release 80% of their encapsulated proteins after 5 h at pH 5.0, but release only 10% at pH 7.4. APCs that phagocytosed the acid-degradable microgels containing ovalbumin were capable of activating ovalbumin-specific cytoxic T lymphocytes. The acid-degradable microgels developed in this article should therefore find applications as delivery vehicles for vaccines targeted against viruses and tumors, where the activation of cytoxic T lymphocytes is required for the development of immunity.