Multifunctional Nanoparticles for Image-Guided Vaccine Delivery in Cancer

描述（由申请人提供）：该项目的目标是开发一种多功能和多用途的纳米颗粒药物递送系统，以优化癌症治疗中疫苗的靶向递送和控释。为了实现这一目标，我们打算用强亲核氨基功能化我们最近开发的氧化铁纳米颗粒的表面，从而允许附着相同肿瘤抗原的多个拷贝。由于纳米颗粒具有强磁化率，它们将提供微观解剖和功能成像反馈，并利用磁共振成像（MRI）治疗癌症。初步数据表明：(1)右旋糖酐包被的氧化铁纳米颗粒适合于用MRI在体内跟踪细胞迁移；（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胺连接剂可以使表面带有胺的右旋糖酐涂层氧化铁纳米颗粒功能化。在这个提议中，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。满载肿瘤抗原的纳米颗粒将被配制成气溶胶，并通过吸入分布到肺部，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，如：(1)考虑到肺部树突状细胞的丰度，该组织是否会成为激活常驻dc的合适目的地；(2)通过吸入分布的肿瘤抗原是否会诱导足够的肿瘤特异性免疫治疗？我们将通过以下具体目标来验证我们的假设：(1)将铁纳米粒子与胺功能化并在表面结合肿瘤抗原，并将抗原-铁纳米粒子制成气溶胶；(2)：发展磁共振成像技术，利用超短自旋回波时间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。

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.