Investigation and design of dendritic peptide bolaamphiphile vectors for siRNA delivery

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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.