NANOPARTICLE DRUG DELIVERY OF MACROMOLECULAR THERAPEUTICS

Abstract

The goal of my senior thesis project was to develop functionalized nanoparticles that are able to undergo endocytosis before escaping the endosome in order to deliver biologics with cytosolic or nuclear targets to the interior of cells. The first part of the project was focused on the synthesis and characterization of Polystyrene / Polystyene-block-Polyethylene Oxide nanoparticles doped with positively charged (Polystyene-Dimethylaminoethyl acrylate) and negatively charged (Polystyrene-Polyacrylic Acid) polymers. Our basic procedure for synthesizing these nanoparticles was the flash nano-precipitation process: mixing tetrahydrofuran containing Polystyrene and a combination of hydrophilic with an antisolvent of water via a confined impingement jet mixer. The second direction of investigation entailed an attempt to achieve better results with lower toxicity than cationic polymer nanoparticles by simulating the action of lytic peptides that viruses use to penetrate cell membranes using simpler ionic and zwitterionic materials that may be more easily synthesized. The experiments involved an attempt to prepare a cationic PBAE polymer with tunable pKa for endosome lysis via a Michael addition of 1,4 butanediol diacrylate and 5-amino-1-pentanol under different reaction conditions, and to characterize the length of the resulting polymer by NMR. This polymer was to be attached to flash nanoprecipitated nanoparticles to form a universal delivery vehicle for macromolecules.