Self-assembled peptide nanostructure delivery sytems for oligonucleotide therapy
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Oligonucleotides are potent therapeutic agents in the treatment of cancer, metabolic, cardiovascular and various hereditary diseases. Despite their great potential, oligonucleotide-based drugs have failed in clinical and pre-clinical studies due to their low cell penetration capacities, short plasma half-lives and rapid clearances. As such, development of delivery systems for oligonucleotide drugs is necessary to protect oligonucleotide based-drugs from renal and reticulo-endothelial system (RES) clearance and as well as to facilitate their delivery within target sites. In this thesis, a peptide nanostructure delivery system was developed to improve these deficiencies and to create an effective carrier for oligonucleotide therapy. Cell penetration capacity and silencing efficiency of a model oligonucleotide drug, Bcl-2 antisense oligonucleotide, was shown to be increased following encapsulation within cell penetrating peptides. In addition, the importance of the geometry of the delivery system in cellular internalization was investigated. The geometry of the nanostructure was shown to be critical in cellular internalization, where nanofibers were observed to be internalized to a greater extent compared to nanospheres. Their cellular uptake mechanisms were also studied and internalization of nanofibers was found to depend on an endocytic pathway whereas nanospheres were internalized via a non-endocytic pathway.
Geometry of the delivery system
Cellular internalization mechanism
Cell penetrating peptides