Cancer specific and organ-avoiding RNA architectures for quantitative imaging

用于定量成像的癌症特异性和器官回避 RNA 结构

• 批准号: 9208386
• 负责人: Bernard Mark Evers
• 金额: $ 29.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208386
• 关键词: Cancer; specific; organ; avoiding; RNA

DESCRIPTION (provided by applicant): Development of image-guided drug delivery systems for real-time monitoring, quantifying and validating the delivery and therapeutic action is very important for both research and clinical applications. Various multifunctional nanoparticles of different materials have been investigated over the last decade as prospective imaging and therapeutic platforms; however, effective strategies to quantitatively evaluate delivery of therapeutic payloads to tumors and metastatic cancer cells in vivo are challenging due to low efficiency in specific cancer targeting and non-specific trapping in vital organs such as, liver an lungs. Our goal is to adopt an innovative RNA nanotechnology approach to construct ultrastable multifunctional RNA Beacons and RNA Dendrimers as image-guided agents for quantitative real-time assessment of tumor and metastatic cancer targeted therapeutic delivery, distribution, uptake and response. We have shown that our RNA nanoparticles are non-toxic, non-immunogenic and capable of penetrating across heterogeneous biological barriers to deliver high doses of therapeutics specifically to solid tumors and metastatic cells in mice with little accumulation in normal organs. This provides an ideal platform for non-invasive imaging of cancer therapeutics in vivo. Our multifunctional RNA nanoparticles will be designed to harbor: (1) imaging modules: NIR fluorophores for in vivo fluorescence imaging; radionuclides for PET/SPECT imaging; and gadolinium contrast agents for MRI; (2) targeting modules: such as RNA aptamers or chemical ligands for binding to cancer specific cell surface receptors resulting in internalization of RNA nanoparticles into cancer cells; and (3) therapeutic modules: siRNAs and anti-miRNA to silence the expression of oncogenic genes. The multifunctional RNA constructs will then be evaluated in our well established colon cancer animal models. We will employ multimodal imaging techniques (NIRF, PET/SPECT and/or MRI) for monitoring the therapeutic delivery process in real-time at various spatial and temporal resolution scales. This approach is based on the consideration that each of the three imaging modalities has advantages, and an integrated approach will lead to synergistic benefits with regards to image-guided therapy.

描述(由申请人提供)：开发用于实时监测、量化和验证递送和治疗作用的图像引导药物递送系统对于研究和临床应用都非常重要。在过去的十年里，不同材料的各种多功能纳米颗粒被作为有前景的成像和治疗平台进行了研究；然而，由于在特定的癌症靶向和重要器官(如肝脏和肺)的非特异性捕获方面的低效率，有效的策略来定量评估向肿瘤和体内转移的癌细胞的治疗有效载荷是具有挑战性的。我们的目标是采用一种创新的RNA纳米技术方法来构建超稳定的多功能RNA信标和RNA树枝状分子，作为图像引导试剂，用于定量实时评估肿瘤和转移性癌症的靶向治疗传递、分布、摄取和反应。我们已经证明，我们的RNA纳米颗粒无毒、无免疫原性，能够穿透异质生物屏障，专门针对小鼠实体瘤和转移细胞提供高剂量的治疗药物，而在正常器官中几乎没有蓄积。这为癌症治疗药物的体内非侵入性成像提供了理想的平台。我们的多功能RNA纳米颗粒将包含：(1)成像模块：用于体内荧光成像的近红外荧光团；用于PET/SPECT成像的放射性核素；以及用于磁共振成像的Gd造影剂；(2)靶向模块：如RNA适配子或化学配体，用于与癌症特定的细胞表面受体结合，从而使RNA纳米颗粒内化到癌细胞内；以及(3)治疗模块：用于沉默癌基因表达的siRNAs和anti-miRNA。然后，我们将在我们已建立的结肠癌动物模型中对多功能RNA结构进行评估。我们将使用多模式成像技术(NIRF、PET/SPECT和/或MRI)在不同的空间和时间分辨率尺度上实时监测治疗过程。这一方法是基于这样的考虑，即三种成像方式各有优势，综合方法将在图像引导治疗方面产生协同效益。