Nanoscale polyionic complexes of biomacromolecules for drug delivery applications

Abstract

Polyelectrolyte complexes attract increasing attention due to their importance in biological sciences and di-verse industrial applications. For example, therapeutic agents (e.g., drugs, proteins, and genes) can be encap-sulated into polyelectrolyte complexes to increase their solubility and stability. They are also used for func-tional surface coatings. In this thesis work, I investigate the formation, stability, and behaviors of the poly-electrolyte complexes of siRNA and proteins for drug delivery applications. First, I construct various siRNA structures using streptavidin and biotin-modified siRNAs to investigate the influence of the siRNA structural change on the polyelectrolyte complexes. Biotin-capped multimeric siRNAs structures show excellent gene silencing activities when complexed with cationic polyelectrolytes. This result suggests that the increased flexibility and charge density of the siRNA structures enables the formation of much compact and stable polyelectrolyte complexes with the cationic polyelectrolytes, leading to in-creased cellular uptake. Furthermore, a diverse range of functionalities can be introduced to the complexes via streptavidin-biotin interactions. This system provides a platform for multifunctional nanoparticle for-mation as demanded without complicated chemical reactions. Second, to increase the stability of polyelectrolyte complexes of siRNA and cationic polyelectrolytes, hydrophobic interactions are introduced. Dimeric siRNA conjugates are synthesized with different hydropho-bic hydrocarbon spacer lengths. The cellular uptake and gene silencing efficiency are increased with increas-ing hydrophobic spacer length. It implies that the hydrophobic interaction, in addition to the electrostatic in-teraction, contributs to the formation of more compact and stable complexes with cationic polyelectrolytes, which results in increased cellular uptake and gene silencing. In addition, the hydrophobic portion of the complexes facilitates...