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: 8883529
• 负责人: Bernard Mark Evers
• 金额: $ 5.13万
• 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 2016-01-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883529
• 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; 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; image guided therapy; imaging agent; imaging modality; in vivo; innovation; mouse model; nano; nanoparticle; non-invasive imaging; prospective; public health relevance; quantitative imaging; radiotracer; response; scaffold; single photon emission computed tomography; stem; temporal measurement; 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、定量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作为前瞻性成像和治疗平台进行了研究;然而，由于特异性癌症靶向和非特异性捕获效率低，定量评估治疗有效负载向体内肿瘤和转移性癌细胞的递送的有效策略具有挑战性。重要器官，例如肝脏和肺部。我们的目标是采用创新的RNA纳米技术方法构建超稳定的多功能RNA Besters和RNA Dendrimers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递送、分布、摄取和反应。我们已经证明，我们的RNA纳米颗粒是无毒的，非免疫原性的，并且能够穿透异质生物屏障，以特异性地向小鼠中的实体瘤和转移性细胞递送高剂量的治疗剂，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纳米颗粒将被设计成具有：（1）成像模块：用于体内荧光成像的NIR荧光团;用于PET/SPECT成像的放射性核素;和用于MRI的钆造影剂;（2）靶向模块：例如RNA适体或用于结合癌症特异性细胞表面受体的化学配体，导致RNA纳米颗粒内化到癌细胞中;和（3）治疗模块：siRNA和抗miRNA沉默致癌基因的表达。然后将在我们良好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输送过程。该方法基于以下考虑：三种成像模式中的每一种都具有优势，并且综合方法将导致关于图像引导治疗的协同益处。