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: 8773989
• 负责人: Bernard Mark Evers
• 金额: $ 34.16万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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/8773989
• 关键词: Adopted; Animal Model; Animals; Architecture; Binding; Biological; Biological Models; Cancer Diagnostics; Cancer Model; Catalytic RNA; Cell Surface Receptors; Cells; Chemicals; Colon Carcinoma; Contrast Media; Dendrimers; Detection; Development; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Dyes; Evaluation; Future; Gadolinium; Gene Silencing; Genes; Goals; Heterogeneity; Image; Imaging Techniques; In Vitro; Injection of therapeutic agent; Iowa; Lead; Ligand Binding; Ligands; Liver; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Methods; MicroRNAs; Molecular; Monitor; Motor; Multimodal Imaging; Mus; Nanotechnology; Nature; Neoplasm Metastasis; Oncogenic; Organ; Positron-Emission Tomography; Process; RNA; RNA Transport; Radioisotopes; Radiolabeled; Radionuclide Imaging; Reporter; Research; Resistance; Resolution; Side; Signal Transduction; Small Interfering RNA; Solid Neoplasm; System; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Urea; aptamer; base; cancer cell; clinical application; design; fluorescence imaging; fluorophore; gadolinium oxide; image guided therapy; imaging modality; in vivo; innovation; mouse model; nano; nanoparticle; non-invasive imaging; prospective; public health relevance; radiotracer; response; scaffold; single photon emission computed tomography; stem; therapeutic siRNA; therapeutic target; trafficking; tumor; uptake

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。过去十年来，人们对不同材料的各种多功能纳米粒子作为前瞻性成像和治疗平台进行了研究；然而，由于特定癌症靶向的效率低以及肝脏和肺等重要器官的非特异性捕获，定量评估体内肿瘤和转移性癌细胞的治疗有效载荷的传递的有效策略具有挑战性。我们的目标是采用创新的 RNA 纳米技术方法来构建超稳定的多功能 RNA 信标和 RNA 树状聚合物作为图像引导剂，用于定量实时评估肿瘤和转移性癌症靶向治疗的传递、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，专门向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积累。这为体内癌症治疗的非侵入性成像提供了理想的平台。我们的多功能 RNA 纳米粒子将被设计为具有：（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 MRI 的钆造影剂； (2)靶向模块：例如RNA适体或化学配体，用于与癌症特异性细胞表面受体结合，导致RNA纳米颗粒内化到癌细胞中； (3) 治疗模块：siRNA 和抗 miRNA，以沉默致癌基因的表达。然后，多功能 RNA 构建体将在我们完善的结肠癌动物模型中进行评估。我们将采用多模态成像技术（NIRF、PET/SPECT 和/或 MRI）以各种空间和时间分辨率尺度实时监测治疗递送过程。这种方法基于以下考虑：三种成像方式各有优点，综合方法将带来图像引导治疗的协同效益。