Murthy Niren, Xu Mingcheng, Schuck Stephany, Kunisawa Jun, Shastri Nilabh, Fréchet Jean M J
Center for New Directions in Organic Synthesis and Department of Chemistry, University of California, Berkeley, and Materials Science Division, Lawrence Berkely National Laboratory, 94720-1460, USA.
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):4995-5000. doi: 10.1073/pnas.0930644100. Epub 2003 Apr 18.
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.
基于蛋白质的疫苗的研发仍然是免疫学和药物递送领域的一项重大挑战。尽管已经鉴定出许多能够对感染性病原体产生免疫的蛋白质抗原，但由于递送问题，基于蛋白质抗原的疫苗研发取得的成功有限。在本文中，合成了一种酸敏性微凝胶材料用于基于蛋白质的疫苗的研发。这些微凝胶的化学设计使其在抗原呈递细胞（APC）吞噬体中发现的轻度酸性条件下发生降解。微凝胶的快速裂解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细胞质中以进行I类抗原呈递。卵清蛋白被包裹在直径为200 - 500 nm的微凝胶颗粒中，这些颗粒通过逆乳液聚合与合成的酸可降解交联剂制备而成。卵清蛋白以pH依赖的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小时后释放其包裹蛋白质的80%，但在pH 7.4下仅释放10%。吞噬了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微凝胶作为针对病毒和肿瘤的疫苗的递送载体应具有应用价值，在这些情况下，免疫的发展需要激活细胞毒性T淋巴细胞。
