Nanoscale delivery vehicles for antigen-based vaccines

描述（由申请人提供）：虽然疫苗已广泛用于预防传染病，但用于治疗癌症的治疗性疫苗接种的概念最近才被引入。虽然动物研究的结果表明，这种新形式的免疫疗法可能非常有效，但迄今为止，人类癌症疫苗的成功率有限，主要原因是效力不足。为了诱导对肿瘤的有效免疫，必须发生两个关键事件：抗原（Ags）必须被递送到树突状细胞（DC），这是已知最强大的抗原递呈细胞，并且这些细胞必须以确保其迁移的方式被激活淋巴器官和有效地将抗原递呈给T细胞。在这项提案中，我们描述了一种新的，通用的和强大的化学方法来制备基于纳米颗粒的Ag疫苗的运载工具。我们的初步研究表明，这些纳米颗粒能够以导致有效的全身免疫的方式将Ag递送到DC。所述颗粒包括酸不稳定组分，所述酸不稳定组分被设计成使得在它们的细胞摄取和运输至吞噬体时，它们容易降解。这诱导渗透压的增加和隔室壁的破坏，使得包封的Ag被释放并递送到ARC细胞质中。我们建议1）除了Ag之外，将特异性激活DC的免疫刺激剂掺入纳米颗粒中; 2）开发新的聚合物支架和组分以改善降解动力学和生物相容性; 3）研究DC特异性配体和替代递送途径的使用以最大化疫苗对DC的靶向;和4）评价我们的疫苗颗粒在荷瘤动物中诱导肿瘤根除的能力。我们的最终目标是创造出一种新的疫苗，这种疫苗整合了免疫学和材料化学领域的最新发展，不仅可以应用于癌症，还可以应用于广泛的其他疾病。这项研究与公共卫生的相关性在于开发新的治疗性纳米颗粒，可用于制造广泛的疫苗，这些疫苗将激活免疫系统以保护和对抗疾病。

DESCRIPTION (provided by applicant): While vaccines have been widely used for the prevention of infectious disease, the concept of therapeutic vaccination for the treatment of cancer has only recently been introduced. Although the results of animal studies suggest that this new form of immunotherapy can be highly effective, to date human cancer vaccines have shown only limited success, due mainly to inadequate potency. Two key events must occur for the induction of effective immunity to tumors: the antigens (Ags) must be delivered to dendritic cells (DCs), the most powerful antigen presenting cells known, and these cells must be activated in a manner that ensures their migration to lymphoid organs and their efficient presentation of Ag to T cells. In this proposal, we describe a new, versatile and robust chemical approach to prepare nanoparticle-based delivery vehicles for Ag-based vaccines. Our preliminary studies indicate that these nanoparticles are capable of delivering Ags to DCs in a manner that leads to potent systemic immunity. The particles include acid-labile components that have been designed such that, upon their cellular uptake and trafficking to the phagosome, they degrade readily. This induces an increase in osmotic pressure and disruption of the compartmental walls so that the encapsulated Ags are freed and delivered into the ARC cytoplasm. We propose to 1) incorporate into the nanoparticles immunostimulatory agents, in addition to Ags, that specifically activate the DCs; 2) develop new polymer scaffold and components for improved degradation kinetics and biocompatibility; 3) investigate the use of DC specific ligands and alternative routes of delivery to maximize targeting of the vaccine to DCs; and 4) evaluate the ability of our vaccine particles to induce tumor eradication in tumor bearing animals. Our ultimate goal is to create a new class of vaccines that integrates the latest developments in the fields of immunology and materials chemistry and that can be applied not only to cancer but also to a wide range of other diseases. The relevance of this research to public health lies in the development of novel therapeutic nanoparticles that can be used to create a broad range of vaccines that will activate the immune system to both protect against and combat disease.