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）：用于实时监控，量化和验证输送和治疗作用的图像引导的药物输送系统的开发对于研究和临床应用都非常重要。在过去的十年中，已经研究了各种不同材料的多功能纳米颗粒，作为前瞻性成像和治疗平台。然而，由于特定癌症靶向和非特异性器官（例如肝脏肺部的肺部）的效率较低，因此在体内定量评估治疗有效载荷向肿瘤和转移性癌细胞的有效策略是具有挑战性的。我们的目标是采用创新的RNA纳米技术方法来构建超强的多功能RNA信标和RNA树枝状聚合物作为图像引导的剂，以实时对肿瘤的实时评估和转移性癌症针对的治疗，分布，摄取和反应。我们已经表明，我们的RNA纳米颗粒是无毒的，无免疫原性的，并且能够穿透在异质生物屏障中，以在正常器官中几乎没有积聚的小鼠中专门针对实体瘤和转移性细胞的高剂量疗法。这为体内癌症治疗剂的非侵入性成像提供了理想的平台。我们的多功能RNA纳米颗粒将被设计为藏有：（1）成像模块：用于体内荧光成像的NIR荧光团；放射性核素用于PET/SPECT成像；和MRI的Gadolinium对比剂； （2）靶向模块：例如与癌症特异性细胞表面受体结合的RNA适体或化学配体，导致RNA纳米颗粒在癌细胞中内化； （3）治疗模块：siRNA和抗miRNA，以使致癌基因的表达保持沉默。然后，将在我们建立的结肠癌动物模型中评估多功能RNA构建体。我们将采用多模式成像技术（NIRF，PET/SPECT和/或MRI）在各种空间和时间分辨率量表下实时监测治疗交付过程。这种方法基于这样的考虑：三种成像方式中的每一种都有优势，并且综合方法将在图像引导的治疗方面带来协同的好处。