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

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。该奖项由加州大学欧文分校材料研究部的生物材料项目授予，旨在研究一种新的可生物降解和环境响应的糖肽共聚物纳米凝胶家族，作为小干扰RNA（siRNA）递送的智能纳米载体。最近发现的siRNA的基因沉默效应作为用于各种疾病治疗的基因治疗的新方法呈现出巨大的潜力。然而，其临床应用的一个主要障碍是缺乏siRNA到靶细胞中的有效递送。在不同的递送载体中，阳离子合成聚合物由于其高的结构灵活性和功能性而特别有前途。已经测试了许多聚合物系统用于siRNA递送，然而，它们相对低的转染效率和高的细胞毒性保证了新的安全和有效的递送系统的进一步发现。根据PI之前的研究？在实验室中，基本的糖肽聚合物结构具有固有的安全性和通用性，为合理设计和优化提供了可能性。通过将许多刺激响应性特征编程到纳米凝胶中，目标是将纳米凝胶-siRNA复合物（纳米复合物）在细胞外运输期间的高稳定性与siRNA一旦到达细胞内目的地的有效释放联合收割机组合。虽然该计划的最终目标是发现真正安全和有效的合成载体的siRNA交付，目前提出的努力将主要集中在探索新的概念，在化学设计和合成的纳米凝胶载体，调查的化学物理性质的siRNA纳米凝胶复合物，并在体外siRNA转染试验使用这些纳米凝胶载体。siRNA的基因沉默能力的发现预示了使用小干扰RNA治疗遗传疾病的巨大治疗潜力。siRNA技术实现临床应用的一个主要障碍是缺乏将siRNA递送到细胞中的有效方法。本研究探索了一种新的环境响应性纳米凝胶方法，用于有效的siRNA递送。该研究的目标是测试纳米凝胶载体的新设计概念，了解纳米凝胶载体的基本结构-性质关系，并最终开发出安全有效的合成载体，可能对生物技术和制药行业产生巨大影响。此外，拟议的多学科研究活动将为研究生和本科生，特别是目前从事这一项目的少数民族学生和女学生提供良好的培训。

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.