RNA Nanotechnology in Cancer Therapy

项目描述（由申请人提供）：本项目旨在组建一个跨学科团队，研究RNA纳米技术，构建多价RNA纳米颗粒，用于特异性靶向和递送癌细胞。RNA分子可以下调癌细胞中特定基因的表达。RNA作为纳米技术和纳米医学中自下而上组装的构建块尤其具有吸引力。RNA可以像DNA一样容易操作，但在结构和功能上具有与蛋白质相似的多功能性。RNA包含单链茎环，用于RNA内部或RNA之间的相互作用，可以作为安装燕尾，在纳米机器组装中提供比外部连接榫的优势。该CNPP操作包括三个主要功能：治疗性RNA纳米颗粒构建的基础研究；治疗性和靶向性部分与RNA纳米颗粒的结合和结合；以及对癌细胞进行特定的治疗。该团队包括在生物医学工程、化学、RNA和DNA纳米技术方面具有强大背景的基础科学家；在核酶和siRNA传递方面具有丰富经验的癌症生物学家；以及制药方面的合作，重点是RNA疗法和动物试验方面的专业知识。该团队将阐明RNA纳米颗粒组装中RNA/RNA相互作用的基本原理，使用phi29马达pRNA系统和RNA连接基序构建含有适体、siRNA、核酶、配体、成像标记或癌症细胞识别和基因沉默药物的多价RNA低聚物。SELEX将开发一种新的方法来筛选稳定和高亲和力的RNA适体，特异性靶向和进入癌细胞。设计同时递送和检测，结合治疗和检测对细胞凋亡的后续治疗效果。交叉、化学修饰和交联等方法可使RNA纳米颗粒在体内稳定。将开发新的发酵方法和工业规模生产方法，以生产大规模稳定的RNA用于临床应用。将在肺癌、卵巢癌、肝癌和白血病动物模型上进行药代动力学、生物分布、毒性、基因沉默效应和癌细胞杀伤等动物试验。相关性（见说明）：癌症是当前和长期的医疗保健危机，治疗需要对靶向细胞的特异性递送进行研究。本应用提出制造RNA纳米颗粒来结合治疗SiRNA、适配体和核糖体来完成靶向递送。将选择治疗成分用于治疗肺癌、卵巢癌、肝癌和白血病。

DESCRIPTION (provided by applicant): This project is to organize an interdisciplinary team to work on RNA nanotechnology by constructing polyvalent RNA nanoparticles for specific targeting and delivery to cancer cells. RNA molecules can down-regulate specific gene expression in cancer cells. RNA is particularly attractive as a building block for bottom-up assembly in nanotechnology and nanomedicine. RNA can be manipulated as easily as DNA, but possesses the versatility in structure and function similar to that of proteins. RNA contains single-stranded stem-loops for intra- or inter-RNA interactions which can serve as mounting dovetails, providing advantages over external linking dowels in nanomachine assembly. This CNPP operation comprises of three major functions: the fundamental studies on therapeutic RNA nanoparticle construction; the conjugation and incorporation of therapeutic and targeting moieties to RNA nanoparticles; and the specific delivery of therapeutics to cancer cells. The team includes basic scientists with strong backgrounds in biomedical engineering, chemistry, and RNA and DNA nanotechnology; cancer biologists with extensive experience in ribozyme and siRNA delivery; and pharmaceutical cooperation focusing on RNA therapeutics with expertise in animal trials. The team will elucidate the principles underlying the RNA/RNA interactions in RNA nanoparticle assembly using phi29 motor pRNA system and RNA junction motifs to build polyvalent RNA oligomers containing aptamer, siRNA, ribozyme, ligand, imaging markers or drugs for cancer cell recognition and gene silencing. A new methodology of SELEX will be developed to screen for stable and high affinity RNA aptamers that target and enter cancer cells specifically. Simultaneous delivery and detection will be designed, combining therapy and detection of subsequent therapeutic effects on apoptosis. Approaches of crossover, chemical modification, and cross-linking will be applied to make RNA nanoparticles stable in vivo. Novel fermentation approaches and industry scale production methods will be developed to produce large-scale stable RNA for clinical applications. Animal trials on pharmacokinetics, bio-distribution, toxicity, gene silencing effects, and cancer cell killing will be carried out on animal models of lung cancer, ovarian cancer, liver cancer, and leukemia. RELEVANCE (See instructions): Cancer is a current and long term health care crisis and treatments necessitate the investigation of specific delivery to target cells. This application proposes to fabricate RNA nanoparticles to incorporate therapeutic SiRNA, aptamers, and ribosomes to accomplish targeted delivery. Therapeutic constituents will be selected for the treatment of lung cancer, ovarian cancer, liver cancer, and leukemia.