De Novo Design of Biodegradable and Environmentally Responsive Saccharide-Peptide Nanogels for siRNA Delivery

用于 siRNA 递送的可生物降解且环境响应的糖肽纳米凝胶的从头设计

• 批准号: 0907688
• 负责人: Zhibin Guan
• 金额: $ 42万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0907688&HistoricalAwards=false
• 关键词: De; Novo; Design; Biodegradable; Environmentally

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)This award by the Biomaterials program in the Division of Materials Research to University of California Irvine is to study a new family of biodegradable and environmentally responsive saccharide-peptide copolymer-based nanogels as smart nanocarriers for small interference RNA (siRNA) delivery. The recently discovered gene silencing effects of siRNA presents tremendous potential as a new approach in gene therapy for various disease treatments. However, one major barrier for its clinical use is the lack of efficient delivery of siRNA into the target cells. Among different delivery vectors, cationic synthetic polymers are especially promising because of their high structural flexibility and functionalities. A number of polymeric systems have been tested for siRNA delivery, however, their relatively low transfection efficiency and high cytotoxicity warrants further discovery of new safe and efficient delivery systems. Based on previous studies from the PI?s laboratory, the basic saccharide-peptide polymer construct is inherently safe and versatile, offering potential for rational design and optimization. By programming a number of stimuli-responsive features into nanogels, the goal is to combine high stability for nanogel-siRNA complexes (nanoplexes) during extracellular trafficking with efficient release of siRNA once reaching intracellular destinations. Whereas the ultimate goal of this program is to discover truly safe and efficient synthetic vectors for siRNA delivery, the current proposed efforts will be primarily focused on exploring new concept in chemical design and synthesis of nanogel vectors, investigation of chemical-physical properties of siRNA-nanogel complexes, and in vitro siRNA transfection assays using these nanogel vectors. The discovery of gene silencing capability of siRNA forecasts tremendous therapeutic potential for treating genetic disease using small interference RNA. One major road block preventing it from realization of clinical applications for siRNA technology is the lack of efficient methods to deliver siRNA into cells. This study explores a novel environmentally responsive nanogel approach for efficienct siRNA delivery. The goal of the study is to test a new design concept of nanogel vectors, understand basic structure-property relationship of the nanogel vectors, and ultimately develop safe and efficient synthetic vectors that can potentially have tremendous impact on biotechnological and pharmaceutical industries. In addition, the proposed multi-disciplinary research activity will provide excellent training for graduate and undergraduate students, especially for minority and women students currently working on this project.

该奖项是根据2009年《美国回收与重新投资法》（公法111-5）获得的，生物材料计划在加利福尼亚大学欧文分校的材料研究部该奖项是为了研究一个新的可生物降解和环境响应式糖精的糖水肽肽肽共聚物的纳米凝胶作为智能的纳米凝胶，作为小型Interference rna（Sirnna sirnna）的智能nanocarriers（sirnna）。最近发现的siRNA基因沉默效应具有巨大的潜力，作为各种疾病治疗的基因治疗方法。但是，其临床使用的一个主要障碍是缺乏有效的siRNA进入靶细胞。在不同的递送载体中，阳离子合成聚合物的结构柔韧性和功能很高，特别有望。已经测试了许多聚合系统的siRNA输送，但是，它们相对较低的转染效率和高细胞毒性需要进一步发现新的安全有效的输送系统。根据PI的实验室的先前研究，基本的糖肽聚合物构建体固有安全且通用，为理性设计和优化提供了潜力。通过将许多刺激响应特征编程到纳米凝胶中，目标是在细胞外运输过程中结合纳米凝胶-sirna复合物（纳米旋转）的高稳定性，一旦达到细胞内目的地，siRNA有效释放。尽管该计划的最终目标是发现siRNA交付的真正安全有效的合成媒介，但目前的提议将主要集中于探索纳米凝胶矢量的化学设计和合成中的新概念，研究sirna-nanogel复合物的化学物理性能，以及使用这些nanogel vectors nangogel vectors。 siRNA的基因沉默能力的发现预测了使用小干扰RNA治疗遗传疾病的巨大治疗潜力。阻止其实现siRNA技术临床应用的一个主要路障是缺乏将siRNA输送到细胞中的有效方法。这项研究探索了一种新型的环境响应纳米凝胶方法，以效率siRNA递送。该研究的目的是测试纳米凝胶矢量的新设计概念，了解纳米凝胶矢量的基本结构 - 性关系，并最终开发出可能对生物技术和制药行业产生巨大影响的安全有效的合成媒介。此外，拟议的多学科研究活动将为研究生和本科生提供出色的培训，尤其是针对目前从事该项目的少数民族和女学生。