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Rational Design of Synthetic Vectors for siRNA Delivery


Despite promising potentials for disease treatment, clinical application of RNAi is greatly limited by the lack of safe and effective delivery vectors. In this dissertation, we aim to achieve efficient siRNA delivery by developing novel synthetic biomaterials through rational molecular design and in-depth structure-property study.

Chapter 1 introduces the background of siRNA delivery. Major challenges in synthetic vector design are discussed, followed by current approaches to overcome these obstacles. Several successful synthetic vectors are surveyed with an emphasis on materials with dendritic architectures.

Chapter 2 describes dendronized polymer (denpol) for efficient siRNA delivery. The denpol architecture combines multivalency of dendrons and flexibility of polymer backbone to achieve strong siRNA binding. Through in vitro screening of a focused denpol library, we identified that histidine and aromatic amino acid functionalized denpols achieved high delivery efficiency with minimum cytotoxicity. Fluorescence trafficking study revealed that aromatic groups enhanced cell uptake and histidine helped endosomal escape. Such combination could also be applied to other systems. Chapter 3 describes tryptophan and histidine functionalized dendritic polyglycerol for siRNA delivery. And chapter 4 investigates the application of tryptophan-histidine combination on a novel bolaamphiphile structure. Compared to normal amphiphiles, bolaamphiphiles do not disrupt cell membrane and thus greatly reduces toxicity. The molecular structure of bolaamphiphiles determines their self-assembly behavior with siRNA and subsequent biological activity. The optimal dendron bolaamphiphile achieved effective silencing at low siRNA concentration.

Chapter 5 highlights the importance of formulation process in delivery. In a stimuli-responsive nanogel system, we found that only in situ cross-linking could effectively encapsulate siRNA and achieve functional delivery.

Chapter 6 describes a novel Ru catalytic system for polyamide synthesis. All the biomaterials we developed in previous chapters are based on polyamides, as the amide bonds provide good chemical stability while maintain biodegradability. Current syntheses of polyamides involve harsh conditions and/or produce stoichiometric amount of toxic waste. We developed the first catalytic polyamidation by dehydrogenation of diols and diamines to achieve high atomic economy with no waste generation. The high catalytic selectivity also offers the opportunity to efficiently incorporate polyamines into the polymer backbone without tedious protection/deprotection steps.

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