Multifunctional Nanoparticles for Image-Guided Vaccine Delivery in Cancer

用于癌症图像引导疫苗输送的多功能纳米颗粒

• 批准号: 8634059
• 负责人: Wellington Pham
• 金额: $ 31.11万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634059
• 关键词: Address; Adjuvant; Aerosols; Amines; Antigens; Area; Biological Assay; Breathing; CD8B1 gene; Cancer Vaccines; Cell Count; Cell Therapy; Cells; Clinical Trials; Complex; Data; Dendritic Cell Vaccine; Dendritic Cells; Destinations; Development; Dextrans; Drug Delivery Systems; Epithelial; Epoxy Compounds; Feedback; Functional Imaging; Galactosylceramides; Goals; Image; Imaging Techniques; Immune response; Immunity; Immunotherapy; Injection of therapeutic agent; Iron; Kinetics; Laboratories; Ligands; Lung; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Mediating; Methods; Monitor; Mucin-1 Staining Method; Mus; Nanotechnology; Natural Immunity; Outcome Study; Physics; Physiologic pulse; Predisposition; Process; Route; Site; Specificity; Surface; System; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translations; Tumor Antigens; Tumor Immunity; Vaccines; adaptive immunity; aerosolized; amino group; antitumor agent; base; cancer therapy; cell motility; cellular imaging; chemokine; clinical application; controlled release; cytokine; design; dextran; efficacy testing; in vivo; innovation; insight; iron oxide; killer T cell; lymph nodes; mouse model; nanoparticle; nanoscale; novel; pre-clinical; response; targeted delivery; theranostics; tumor; tumor growth; vaccine delivery

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.

描述（由申请人提供）：该项目的目标是开发一种多功能、多重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对最近开发的氧化铁纳米粒子的表面进行功能化，从而允许附着多个相同肿瘤抗原的拷贝。由于纳米粒子具有很强的磁化率，因此它们将使用磁共振成像（MRI）提供递送及其在癌症治疗中的效果的微观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使用 MRI 进行体内细胞迁移跟踪； (ii) 我们实验室开发和使用的方法能够追踪淋巴结中的少量细胞； （iii）我们开发的新型环氧化物胺连接体可以用表面上的胺对葡聚糖包覆的氧化铁纳米颗粒进行功能化。在该提案中，我们假设胺化氧化铁纳米粒子提供的多价性可以作为癌症治疗的平台。负载肿瘤抗原的纳米颗粒将被配制为气雾剂并通过吸入分布到肺部以诱导抗肿瘤免疫。这些努力将致力于寻找细胞治疗中基本问题的答案，例如（i）考虑到肺部有丰富的树突状细胞，该组织是否是激活常驻树突状细胞的合适目的地，以及（ii）通过吸入分配肿瘤抗原是否会诱导足够的肿瘤特异性免疫治疗？我们将通过追求以下具体目标来检验我们的假设：（1）用胺功能化铁纳米颗粒并在表面结合肿瘤抗原，并将抗原-铁纳米颗粒配制为气溶胶； (2)：开发 MRI 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功效并评估肿瘤反应。