Targeted Delivery of Therapeutic Peptides Using Supramolecular Nanomaterials to Drug Intracellular Protein-Protein Interactions in Cancer

The overall goal of my thesis work was to develop supramolecular nanocarriers to deliver therapeutic peptides to and into diseased cells. I primarily applied this to therapeutic peptides that inhibit protein-protein interactions (PPIs) cancer cells rely on to avoid therapeutic-induced cell death. In Chapter 1, I introduce the importance of PPIs as therapeutic targets in cancer, why they are commonly considered "undruggable" targets, and how supramolecular nanomaterials can be used to deliver peptide therapeutics to and into cancer cells to overcome these obstacles. In Chapter 2, we used a peptide amphiphile micelle nanocarrier to deliver a BIM BH3 peptide into cells to reactivate apoptosis. While the peptide alone is cell impermeable and therefore therapeutically inert, attaching it to a lipid tail facilitated its cellular uptake, and an endosome-cleavable linker facilitated the peptide's release after uptake to drive intracellular accumulation and pro-apoptotic efficacy. In Chapter 3, I present our work identifying the synthesis and purification conditions in which ester-containing peptide amphiphiles are stable, including an optimized synthesis and purification strategy that avoids ester hydrolysis byproducts. This optimized synthesis and purification strategy is then used to create stapled peptide amphiphile micelles designed to reactivate p53, and their biological efficacy is evaluated. In Chapter 4, we used CD19-targeted polymersomes to deliver an MCL-1 inhibiting stapled peptide to and into DLBCL cells to reactivate cell death. Using this platform for targeted, intracellular delivery, the efficacy of stapled peptides could be greatly enhanced, and we used this to target the synergistic combination of p53 reactivation and MCL-1 inhibition. In Chapter 5, I discuss the relative strengths, weaknesses, and contributions of our nanocarriers for intracellular delivery of peptide therapeutics. Lastly, future directions are described that could advance these lines of research toward clinical applicability.