Peptide-Drug Conjugates: From Supramolecular Polymers to Covalent Polymeric Networks

Hydrogels provide an alternative to traditional medication delivery, which is of particular interest in creating a long-acting release regimen due to their superior biocompatibility and diverse mechanical properties. My work in this thesis focuses on designing peptide drug conjugates as a versatile, multifunctional drug delivery system to address diverse therapeutic issues. Supramolecular polymers generated by the accumulation of individually weak non-covalent interactions possess a distinct linear release profile, which is particularly useful for sustained long-term release of therapeutic. On the other hand, covalent polymeric hydrogels have more mechanical characteristics than supramolecular hydrogels. In this thesis, we aim to exploit the two different hydrogenation strategy demonstrate the potential of peptide-drug conjugates in distinct therapeutic needs. Our strategy is to attach the current FDA-approved drug into a hydrogenator through a biodegradable linker to create a peptide-based prodrug. In Chapter 2, we demonstrated that supramolecular polymers constituted by the hydrophilic antiretroviral (ARV) agent are promising supramolecular hydrogel that enables a linear, sustained release of ARV agents over weeks. In Chapter 3, using a Fe(III) coordinating supramolecular peptide polymer, we demonstrated that supramolecular hydrogelators that are dependent on the supramolecular interaction, and reversible gelation can be easily achieved by ion chelation. Moreover, based on the peptide-conjugates platform, we have the possibility of transforming our peptide prodrugs into a dual-function therapeutic sealant. We highlighted that through weak non-covalent interaction with anions within the hydrogel network. The hydrogel leverages the nanoconfinement effect to serve as a self-tunable synthetic drug delivery system. Lastly, we recognize that fast, reliable, and high-throughput synthesis of peptide conjugates can greatly improve our ability to discover new delivery platforms. We developed a fully automated flow peptide synthesizer that can accomplish a number of difficult conjugation as well as reduce the peptide synthesis time by up to 50 folds. Collectively, I envision that my work presented in this thesis would yield an in-depth understanding of supramolecular hydrogel and covalent hydrogel constructed by peptide-based materials and shed light on transforming hydrogel as a more adaptive and reliable delivery platform for new therapeutic applications