UC San Diego

Nanomedicine is a research field that has recently made significant progress in the areas of drug delivery. A drug delivery vehicle must be able to carry a therapeutic cargo and be able to reach the target tissue and the intended intracellular target or compartment. This dissertation will focus on two major applications of drug delivery vehicles and novel improvements in these areas. The first area is vaccine delivery, where sensitive biological cargo must be delivered to and activate immune cells. A new peptide adjuvant called Hp91 was chosen to be co-delivered to dendritic cells along with an antigen to ensure activation. The vaccine drug delivery vehicle designed to deliver these biomolecules consists of a poly(lactic-co- glycolic acid) (PLGA) core with the antigen encapsulated inside and the peptide adjuvant either co-encapsulated or conjugated to the outside. The PLGA successfully protected the protein and peptide from degradation, maintaining its activity. The vaccine delivery vehicles showed a marked improvement over free Hp91 in both human and mouse dendritic cell activation, with a maximum of 44 fold increase in IL-6 stimulation when the peptide was conjugated to the surface. The second area of research presented here is systemic drug delivery. For systemic delivery, long circulation is a desirable characteristic and poly(ethylene glycol) (PEG) is the current state of the art. However, PEG presents two challenges: 1. PEG can hinder the nanoparticle from entering the cytosol across the endosomal or cellular membrane, and 2. PEG can sometimes induce immunogenicity resulting in accelerated blood clearance after repeated dosing. A novel PEG shedding nanoparticle is presented as a solution to the first challenge. The ability to shed the PEG layer in response to a reduction in pH allows a fusogenic lipid layer to be exposed, which promotes membrane disruption. For patients who respond immunogenically to PEG, a biomimetic apolipoprotein coating to replace PEG altogether is presented. Apolipoprotein A1 is shown here to stabilize PLGA nanoparticles and increase their circulation half-life beyond that of the traditional PEG coating. These drug delivery vehicles were engineered from the foundation of a biodegradable, biocompatible PLGA polymer core with characteristic surface properties designed to overcome these specific challenges to drug delivery