Design of Optimized Peptide-Targeted Nanoparticles for Accomplishment of Selective Drug Delivery to Cancer Cells and Development of Inhibitors for Food Allergic Reactions

This dissertation describes two main research topics that are associated with the development of effective treatments for the common diseases, cancer and allergy. The 1^st part of this dissertation will describe the design, synthesis, characterization, and optimization of peptide-targeted liposomal nanoparticles that show enhanced selectivity to cancer cells including HER2+ breast cancer, CD22+ blood cancer, GRP78+ metastatic breast cancer, and multiple myeloma. Targeted nanoparticle drug delivery systems have widely been investigated to combat a variety of cancers, however, have not yet successfully translated into the clinic. For successful clinical translation, we employed our synthetic strategy that enables reproducible and reliable nanoparticle production with high precision in targeting functionalities. Additionally, we exploited multivalency with moderate affinity receptor-binding peptides as targeting moieties of nanoparticles. Multiple nanoparticle design parameters were both in vitro and in vivo optimized to accomplish enhanced target cancer cell selectivity in order to improve tumor growth inhibition efficacy of chemotherapeutic agents with minimal toxicity. We demonstrated that the targeted nanoparticle formulations outperformed non-targeted counterparts given enhanced anti-tumor efficacy via tumor cell-selective uptake with high therapeutic indices. This suggests a high therapeutic potential of the peptide-targeted nanoparticles to improve patient outcomes in the clinic.

The 2^nd part of this dissertation will describe the development of inhibitors for food allergic reactions. Currently, there are no treatments that effectively prevent allergic reactions. Allergic reactions are triggered by crosslinking of several Immunoglobulin E (IgE) antibodies on immune cells with multiple epitopes on an allergen. In light of this, a key point in developing preventative allergy medicine is to inhibit epitope-IgE interactions. By using nanoallergen platform displaying epitope alone or in combination, we determined and ranked epitope of importance according to epitope immunogenicity. This information was implemented to generate various covalent heterobivalent inhibitor (cHBI) mixtures to test their inhibition efficacy for allergic response. The results demonstrated > 90% of inhibition of allergic response mediated by crude peanut extract and a major shrimp allergen, Pen a 1. Although further studies are necessary, these promising results provide evidence for the potential of nanoallergens and cHBIs for the diagnosis and treatment of food allergies.