RNA Nanotechnology in Cancer Therapy

描述(申请人提供)：这个项目是组织一个跨学科的团队，通过构建多价RNA纳米颗粒来研究RNA纳米技术，以特定的靶向和输送到癌细胞。RNA分子可以下调癌细胞中特定基因的表达。在纳米技术和纳米医学中，RNA作为自下而上组装的构件特别有吸引力。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包含用于RNA内或RNA间相互作用的单链茎环，可用作安装燕尾钉，在纳米机械组装中提供了比外部链接销钉更好的优势。这种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纳米颗粒的偶联和掺入；以及向癌细胞特异性输送治疗药物。该团队包括在生物医学工程、化学以及RNA和DNA纳米技术方面拥有强大背景的基础科学家；在核酶和siRNA输送方面拥有丰富经验的癌症生物学家；以及专注于RNA疗法的制药合作，具有动物试验方面的专业知识。该团队将利用phi29马达PRNA系统和RNA连接基序，阐明RNA纳米颗粒组装中RNA/RNA相互作用的原理，以构建包含适体、siRNA、核酶、配体、成像标志物或用于癌细胞识别和基因沉默的药物的多价RNA寡聚体。将开发一种新的SELEX方法来筛选稳定和高亲和力的RNA适体，这些适体可以特异性地靶向并进入癌细胞。将设计同时提供和检测，结合治疗和检测随后对细胞凋亡的治疗效果。将采用交叉、化学修饰和交联的方法使RNA纳米粒子在体内稳定。将开发新的发酵方法和工业化生产方法来生产大规模稳定的RNA用于临床应用。将在肺癌、卵巢癌、肝癌和白血病的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的动物试验。相关性(见说明)：癌症是当前和长期的卫生保健危机，治疗需要对靶细胞的特定传递进行调查。这项应用建议制造RNA纳米颗粒，以结合治疗性siRNA、适体和核糖体来实现靶向递送。治疗成分将用于肺癌、卵巢癌、肝癌和白血病的治疗。

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.