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Nucleic acid based drugs such as plasmid DNA (pDNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), micro RNA (miRNA), and both antisense and antigene oligonucleotides, are potentially potent and specific compounds for therapeutic applications. Many major life threatening ailments might be treated using these molecules, and many polynucleotide products are currently in advanced clinical development. However, their successful therapeutic application is hindered due to limited delivery to their site of action in either the cytosol or the nucleus of a cell. Some of the barriers in the path of successful delivery of these biomolecules to their site of action have been addressed. However, endosomal entrapment followed by maturation to lysosomes and degradation of these compounds inside the cell is one remaining major hurdle. This dissertation describes two novel siRNA delivery techniques which present distinct advantages in their respective areas of application while, at the same time, constitute promising platforms for developing therapeutic biologicals. Chapter 2 focuses on liposomal delivery vehicles containing hydrophobic nanoparticles in their bilayers, which encapsulate the nucleic acid based drugs and promote endosomal escape by nanoparticle induced fusion with the endosomal membranes. Specifically we use metal nanoparticles in specialized liposomes for the efficient delivery of small interfering RNA (siRNA). Manuscript 2 focuses on novel chiral cationic polymers – polyethyleneimines (PEIs) – that form complexes with the negatively charged nucleic-acid based drugs and promote endosomal escape via a proton sponge effect. Specifically we use of chiral cationic polyamines for two intriguing applications: fabrication of chiral covalentlylinked microcapsules, and enantiospecific delivery of siRNA to Huh 7 cells. We found that two of the designed polymers improved transfection efficiency relative to commercially available transfection reagents with lower cell toxicity. In total this dissertation presents work that demonstrates novel and efficient delivery strategies that promote endosomal escape and enhance the intracellular activity of nucleic acid based drugs.

Novel Methods for Delivering and Promoting the Endosomal Escape of Nucleic Acid Based Drugs: Chiral Polyamines and Hydrophobic Nanoparticle-Containing Liposomes