Graduation Semester and Year
2022
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
He Dong
Abstract
Peptide self-assembly offers an effective method to generate supramolecular nanomaterials with much higher stability than traditional monomeric peptides. The materials exhibit well-organized hierarchical structures and high resistance toward proteolysis and have been utilized extensively in various biomedical applications. Furthermore, due to the prevalence of non-covalent interactions, these structures are highly dynamic. The dynamic nature is beneficial for the design and synthesis of smart, trigger-responsive peptide selfassembly under specific stimulus, in particular various stimuli associated with disease conditions. In Chapter 1, I will introduce different types of peptide building blocks used for the construction of peptide self-assembly. I will further discuss the design of triggerresponsive peptide self-assembly that are formed under disease-specific triggers such as pH, redox and enzymes. In Chapter 2, I will focus on the design, synthesis, and characterization of a reductiveresponsive self-assembled peptide nanofibers, to selectively target therapeutics to tumor cells with high levels of glutathione. The peptide nanofibers exhibit supramolecular-structure dependent cell penetrating activity and can be controlled with a reductive tumor microenvironment. The reduction-dependent structure and activity were thoroughly investigated using combined biophysical methods and in vitro cell-based assay. In Chapter 3, I conducted a more systematic design approach to understand the relationship between supramolecular structure and cell penetrating activity. A small library of multidomain peptides (MDPs) with a general sequence of Kx(QW)6Ey was synthesized and used to probe the supramolecular structure-dependent cell penetrating activity. It was found that cell penetrating activity is dictated by both supramolecular stability and conformational flexibility of the charged domain. Preliminary screening studies identified K10(QW)6E3 as the self-assembling precursor to form nanofibers with most potent cell penetrating activity. This sequence was further selected for the construction of enzyme-responsive cell penetrating nanofibers for tumor cell targeting, which will be described in Chapter 4. In Chapter 4, I will discuss my efforts on a more advanced design and synthesis of peptide nanofibers with enzymatic-controlled cell penetrating activity. This work could open new avenues for cancer imaging and therapy due to their potential of targeting overexpressed enzymes in different cancer tissues. Specifically, we synthesized a new family of MDPs that can undergo enzyme-mediated molecular transformation and supramolecular assembly to form nanofibers. The MDP is designed to have three modules, a membrane-active selfassembling (SA) module, a cationic capping (CC) module and labile linker (LL) module. The hypothesis is in the presence of the cationic CC domain, due to the abundance of the cationic charges and increased electrostatic repulsion, MDPs do not self-assemble and therefore have weak membrane activity. When the external stimulus is applied under specific cellular condition, the LL domain is cleaved to release the CC domain. Consequently, the ability of MDPs to self-assemble is restored to form nanofibers with improved membrane activity. As a proof-of-concept study, we chose matrix metalloproteinase 2, MMP-2 as our initial cellular target due to its overexpression by cancer cells. We synthesized an MDP consisting of an MMP-2 responsive substrate as the linker and observed high cell penetrating activity in the presence of MMP-2. In vitro cell-based assay supports our design based on the therapeutic efficacy against cancer cells with and without endogenous MMP-2. In Chapter 5, I will shift gear and discuss our recent work for the development of pHresponsive peptide materials which have potential for both anticancer and antimicrobial therapy development. This approach is based on the self-assembly of peptides containing unnatural ionic amino acids with an aliphatic tertiary amine side chain. These residues generally have a high pKa value in the basic pH range and may be less useful for the design of biomaterials. We found that when they are incorporated in a peptide self-assembly, the hydrophobic microenvironment within the assembly shifts their pKa significantly from a basic pH to a more biologically relevant pH in the weakly acidic range, therefore greatly boosting their therapeutic potential. I will discuss in detail the synthesis, structural characterization and antimicrobial activity of these pH-responsive peptide self-assembly.
Keywords
Peptide self-assembly, Stimuli-responsive
Disciplines
Chemistry | Physical Sciences and Mathematics
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Yang, Su, "Stimuli-Responsive Peptide Self-Assembly for Therapeutic Delivery" (2022). Chemistry & Biochemistry Dissertations. 265.
https://mavmatrix.uta.edu/chemistry_dissertations/265
Comments
Degree granted by The University of Texas at Arlington