Nanoscale delivery vehicles for antigen-based vaccines

用于基于抗原的疫苗的纳米级运载工具

• 批准号: 7124315
• 负责人: JEAN M FRECHET
• 金额: $ 47.74万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124315
• 关键词: biomaterial development /preparation; biotechnology; dendritic cells; drug delivery systems; immunomodulators; laboratory mouse; leukocyte activation /transformation; microcapsule; neoplasm /cancer vaccine; polymers; tumor antigens; vaccine development

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.

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。尽管动物研究的结果表明这种新形式的免疫疗法非常有效，但迄今为止，人类癌症疫苗仅取得了有限的成功，这主要是由于效力不足。为了诱导对肿瘤的有效免疫，必须发生两个关键事件：抗原 (Ag) 必须被递送至树突状细胞 (DC)（已知最强大的抗原呈递细胞），并且这些细胞必须以确保其迁移的方式被激活淋巴器官及其将 Ag 有效呈递给 T 细胞。在本提案中，我们描述了一种新的、多功能且强大的化学方法来制备基于纳米颗粒的疫苗载体。我们的初步研究表明，这些纳米颗粒能够以产生强大的全身免疫的方式将抗原递送至树突状细胞。这些颗粒包含对酸不稳定的成分，这些成分经过精心设计，一旦被细胞摄取并运输到吞噬体，它们就很容易降解。这会导致渗透压增加和室壁破坏，从而使封装的 Ag 释放并输送到 ARC 细胞质中。我们建议 1) 除了 Ag 之外，将免疫刺激剂纳入纳米颗粒中，特异性激活 DC； 2）开发新的聚合物支架和组件以改善降解动力学和生物相容性； 3) 研究 DC 特异性配体的使用和替代递送途径，以最大限度地提高疫苗对 DC 的靶向性； 4) 评估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一类新型疫苗，融合免疫学和材料化学领域的最新进展，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型治疗性纳米颗粒，可用于制造多种疫苗，激活免疫系统以预防和对抗疾病。