Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Prof. Wei-Ping Mei

Abstract

RNA interference (RNAi) therapy is promising for treating various diseases but the delivery of small interfering RNA (siRNA) is difficult. To overcome the technical difficulties of siRNA delivery, an efficient and targeted delivery of siRNA is required for efficient RNAi therapy. Single-walled carbon nanotubes (CNT) has been used for nucleic acid delivery such as siRNA delivery. It has been found that CNT can gain entry into the cells by a diffusion-like mechanism which was called “nano-needle”. However, the solubility of CNT is low in most of the solvents including water. Functionalization of CNT can be carried out to enhance the solubility of the CNT in water and non-covalent functionalization of CNT is easy to be carried out. Poly(ethylenimine) (PEI) is a cationic polymer and it has been shown to disperse CNT in water. Also, it can deliver nucleic acids including siRNA. However, it is not very efficient at delivering siRNA unless adequately modified.

Three different modifications on PEI were carried out. These polymers and the dispersed CNT were characterized and siRNA delivery capacities of the CNTs were examined in vitro and in vivo. The first was lipid-poly(ethylene glycol) (PEG) conjugated PEI. The second polymer was succinic acid conjugated PEI and the dispersed CNT was used topically in a melanoma model delivering Braf siRNA. The tumor progression was reduced dramatically. Following this work, folic acid, a ligand which target cancer cells was conjugated to the PEG and succinic acid modified PEI. The dispersed CNT was used for systematic delivery of mTOR siRNA in a melanoma model. The tumor progression was inhibited significantly.

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