Investigation and design of dendritic peptide bolaamphiphile vectors for siRNA delivery

用于 siRNA 递送的树突肽 bola 两亲载体的研究和设计

• 批准号: 1609946
• 负责人: Zhibin Guan
• 金额: $ 45万
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1609946&HistoricalAwards=false
• 关键词: Investigation; design; dendritic; peptide; bolaamphiphile

Technical:The goal of this project is to understand the basic physiochemical properties of a new bolaamphiphile (bola) vector system for siRNA delivery and to design new pH-responsive bolas for improved siRNA delivery efficiency. Despite the tremendous potential of RNAi for therapeutics, the lack of safe and effective delivery vehicles hampers the clinical promise of siRNA. Recently the PI's lab has demonstrated a new design of bolaamphiphiles as promising synthetic vectors for siRNA delivery. The bolas show high efficiency and low cytotoxicity for intracellular siRNA delivery, and fluorocarbon bolas also show excellent serum stability. Despite the excellent performances for bolas, many fundamental questions remain unanswered. This project details PI's plans to address several key questions for this new delivery system. The first major aim of the study is to combine both experimental and computational studies to understand the fundamental properties of bola/siRNA complexes, such as the structure and morphology of the complexes, binding affinity and stability of the complexes, as well as how do they interact with serum and membranes. The fundamental insight gained in the first aim will enable to design more effective bola vectors for siRNA delivery. In the second aim PI proposes a specific design of acid-labile bolas for improving the efficiency for siRNA transfection. The proposed multi-disciplinary research activity will provide students excellent training in many areas including organic/polymer synthesis, biomaterials, nanomaterials, and biology. This will provide great opportunities to train graduate and undergraduate students, especially for minority and women students currently working on this project. The PI is also strongly committed to various K-12 outreach programs that are aimed to excite the younger generation with science and to enhance general public understanding and appreciation of chemical sciences and technologies.Non-technical:RNA interference (RNAi) technology has demonstrated tremendous utility both for fundamental biological research and for disease treatments. The high potency and specificity of gene silencing induced by small interfering RNA (siRNA) makes this technology particularly promising for treatment of various diseases including cancer, viral infections, obesity and diabetes. One major roadblock 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 molecular delivery system for safe and efficienct siRNA delivery. The goal of this project is to understand the basic chemi-physical properties of a new molecular delivery system for siRNA delivery and to design new stimuli-responsive delivery molecules for improved siRNA delivery efficiency. Ultimately, the knowledge gained from this study will facilitate the development of safe and efficient siRNA delivery vectors that can 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.

技术：该项目的目标是了解用于siRNA递送的新型bola两亲物（bola）载体系统的基本理化性质，并设计新的pH响应bola以提高siRNA递送效率。尽管RNAi具有巨大的治疗潜力，但缺乏安全有效的递送载体阻碍了siRNA的临床前景。最近，PI的实验室已经证明了bola两亲物的新设计作为用于siRNA递送的有希望的合成载体。该bolas显示出用于细胞内siRNA递送的高效率和低细胞毒性，并且氟碳bolas还显示出优异的血清稳定性。尽管bolas表现出色，但许多基本问题仍未得到解答。这个项目详细介绍了PI的计划，以解决这个新的交付系统的几个关键问题。本研究的第一个主要目的是联合收割机结合实验和计算研究来了解bola/siRNA复合物的基本性质，例如复合物的结构和形态，复合物的结合亲和力和稳定性，以及它们如何与血清和膜相互作用。在第一个目标中获得的基本见解将能够设计用于siRNA递送的更有效的bola载体。在第二个目标中，PI提出了酸不稳定bolas的特定设计，用于提高siRNA转染的效率。拟议的多学科研究活动将为学生提供有机/聚合物合成、生物材料、纳米材料和生物学等多个领域的优秀培训。这将为培训研究生和本科生，特别是目前从事该项目的少数民族学生和女学生提供很好的机会。PI还致力于各种K-12推广计划，旨在激发年轻一代的科学和提高公众对化学科学和技术的理解和欣赏。非技术：RNA干扰（RNAi）技术在基础生物学研究和疾病治疗方面都表现出巨大的实用性。由小干扰RNA（siRNA）诱导的基因沉默的高效力和特异性使得该技术特别有希望用于治疗各种疾病，包括癌症、病毒感染、肥胖和糖尿病。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。本研究旨在探索一种安全有效的siRNA分子传递系统。该项目的目标是了解用于siRNA递送的新分子递送系统的基本化学物理性质，并设计新的刺激响应性递送分子以提高siRNA递送效率。最终，从这项研究中获得的知识将促进安全有效的siRNA递送载体的开发，这将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。