Cancer specific and organ-avoiding RNA architectures for quantitative imaging

描述（由申请人提供）：开发用于实时监测、量化和验证给药和治疗作用的图像引导给药系统对研究和临床应用都非常重要。在过去的十年中，各种不同材料的多功能纳米颗粒被研究作为前瞻性成像和治疗平台；然而，在体内定量评估肿瘤和转移性癌细胞的治疗有效载荷递送的有效策略具有挑战性，因为特异性靶向癌症的效率较低，而肝和肺等重要器官的非特异性捕获效率较低。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树突状物，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，能够穿透异质生物屏障，提供高剂量的治疗药物，特别是对小鼠的实体瘤和转移细胞，在正常器官中几乎没有积累。这为体内肿瘤治疗的非侵入性成像提供了一个理想的平台。我们的多功能RNA纳米颗粒将被设计为包含：(1)成像模块：用于体内荧光成像的近红外荧光团；PET/SPECT成像用放射性核素；MRI用钆造影剂；(2)靶向模块：如RNA适体或化学配体，与癌症特异性细胞表面受体结合，使RNA纳米颗粒内化到癌细胞中；(3)治疗模块：sirna和anti-miRNA，沉默致癌基因的表达。多功能RNA结构将在我们已经建立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）在不同的空间和时间分辨率尺度上实时监测治疗递送过程。这种方法是基于考虑到三种成像方式中的每一种都有优势，综合方法将在图像引导治疗方面产生协同效益。

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.