Investigation and design of dendritic peptide bolaamphiphile vectors for siRNA delivery

技术：本项目的目标是了解一种用于siRNA传递的新的Bola两亲性(BOLA)载体系统的基本物理化学性质，并设计新的pH响应性Bola以提高siRNA的传递效率。尽管RNAi在治疗方面具有巨大的潜力，但缺乏安全有效的递送工具阻碍了siRNA的临床前景。最近，PI的实验室展示了一种新的波拉两亲性分子设计，作为有希望的siRNA传递的合成载体。在细胞内传递siRNA方面，BLOAS表现出高效率和低细胞毒性，而氟碳BLOAS也表现出极好的血清稳定性。尽管博拉斯的表现非常出色，但许多基本问题仍然没有得到解答。该项目详细说明了PI为解决这一新交付系统的几个关键问题而制定的计划。该研究的第一个主要目的是将实验和计算研究相结合，以了解BolA/siRNA复合体的基本性质，如复合体的结构和形态，复合体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使我们能够设计更有效的Bola载体来传递siRNA。在第二个目标中，PI提出了一种特定的设计，以提高siRNA的转染率。拟议的多学科研究活动将为学生提供许多领域的优秀培训，包括有机/聚合物合成、生物材料、纳米材料和生物学。这将为培养研究生和本科生提供很好的机会，特别是对目前从事这一项目的少数民族和女性学生。非技术方面：RNA干扰(RNAi)技术在基础生物学研究和疾病治疗方面显示出了巨大的实用价值。由小干扰RNA(SiRNA)诱导的基因沉默的高效性和特异性使这项技术在治疗癌症、病毒感染、肥胖和糖尿病等多种疾病方面具有特别的前景。阻碍其实现siRNA技术临床应用的一个主要障碍是缺乏有效的方法将siRNA运送到细胞中。本研究探索了一种安全高效的siRNA分子递送系统。本项目的目标是了解一种新的siRNA递送分子递送系统的基本物理化学性质，并设计新的刺激响应递送分子来提高siRNA递送效率。最终，从这项研究中获得的知识将有助于开发安全高效的siRNA递送载体，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提供极好的培训，特别是为目前在该项目工作的少数群体和女性学生提供培训。

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.