Multifunctional Nanoparticles for Image-Guided Vaccine Delivery in Cancer

描述(申请人提供)：该项目的目标是开发一种多功能和多元化的纳米颗粒药物输送系统，以优化癌症治疗中疫苗的靶向输送和受控释放。为了实现这一目标，我们打算对我们最近开发的具有强烈亲核氨基的氧化铁纳米颗粒的表面进行功能化，从而允许附着多个相同的肿瘤抗原副本。由于纳米粒子具有很强的磁敏性，它们将利用磁共振成像(MRI)提供关于递送及其在癌症治疗中的效果的显微解剖和功能成像反馈。初步数据表明：(I)葡聚糖包被的氧化铁纳米颗粒适合于使用MRI在体内跟踪细胞的迁移；(Ii)我们实验室开发和使用的方法能够跟踪淋巴结中的少量细胞；(Iii)我们开发的新型环氧化胺连接物可以使葡聚糖包被的氧化铁纳米颗粒表面带有胺的官能化。在这项提案中，我们假设胺化氧化铁纳米颗粒所提供的多价性可以作为癌症治疗的平台。携带肿瘤抗原的纳米颗粒将被制成气雾剂，通过吸入分配到肺部，以诱导抗肿瘤免疫。这些努力将寻求基于细胞治疗的基本问题的答案，例如(I)鉴于肺内树突状细胞的丰富，该组织是否是激活常驻树突状细胞的合适目的地，以及(Ii)通过吸入的肿瘤抗原分布是否能诱导足够的肿瘤特异性免疫治疗？我们将通过追求以下具体目标来验证我们的假设：(1)将铁纳米颗粒与胺作用，并将肿瘤抗原偶联在表面，将抗原-铁纳米颗粒制成气雾剂；(2)：开发磁共振技术，利用超短自旋回波时间来评估磁溶胶疫苗在肺部的分布。最后，我们将测试肿瘤抗原-纳米颗粒磁溶胶疫苗对荷瘤小鼠的疗效，并评估肿瘤反应。 公共卫生相关性：该项目描述了基于纳米技术的综合平台的开发，用于多功能和多用途的癌症疫苗递送系统。氧化铁纳米颗粒将与肿瘤抗原衍生化，并以气雾剂的形式分布到肺部。核磁共振成像将被用来跟踪交付。

DESCRIPTION (provided by applicant): The goal of this project is to develop a multifunctional and multiplexed nanoparticle-based drug delivery system in order to optimize the targeted delivery and controlled release of vaccine in cancer therapy. To achieve this, we intend to functionalize the surface of our recently developed iron oxide nanoparticles with strong nucleophilic amino groups, thus allowing the attachment of multiple copies of identical tumor antigens. Since the nanoparticles have strong magnetic susceptibility, they will provide microanatomical and functional imaging feedback of the delivery and its effect in cancer therapy using magnetic resonance imaging (MRI). Preliminary data indicate that (i) dextran-coated iron oxide nanoparticles are suitable for in vivo tracking of cell migration using MRI; (ii) the method developed and employed in our laboratory enables the tracking of a small number of cells in the lymph nodes; (iii) the novel epoxide amine linker we developed can functionalize dextran-coated iron oxide nanoparticles with amines on the surface. In this proposal, we hypothesize that the multivalency afforded by the aminated iron oxide nanoparticles can serve as a platform for cancer therapy. The tumor antigen-laden nanoparticles will be formulated as an aerosol and distributed to the lungs via inhalation to induce antitumor immunity. These efforts will be pursued to seek answers to the fundamental questions in cell- based therapy such as (i) given the abundance of dendritic cells in the lungs, will this tissue be a suitable destination at which o activate resident DCs and (ii) does the distribution of tumor antigens via inhalation induce sufficient tumor-specific immunotherapy? We will test our hypothesis by pursuing the following specific aims: (1) Functionalize iron nanoparticles with amines and conjugate the tumor antigens on the surface, and formulate the antigen-iron nanoparticles as an aerosol; (2): Develop MRI techniques to assess the distribution of magnetosol vaccine in the lungs using ultra-short spin echo time. Finally, we will test the efficacy of tumor antigen-nanoparticle magnetosol vaccine on tumor-bearing mice and assess tumor response. PUBLIC HEALTH RELEVANCE: This project describes the development of integrated nanotechnology-based platforms for multifunctional and multiplexed vaccine delivery system in cancer. The iron oxide nanoparticles will be derivatized with tumor antigens and distributed to the lungs as aerosol. Magnetic resonance imaging will be used to track the delivery.